Compounds useful for treating premature aging and in particular progeria

ABSTRACT

The present invention relates to compound (I) wherein: means a pyridazine, a pyrimidine or a pyrazine group, R independently represent a hydrogen atom, a halogen atom or a group chosen among a —CN group, a hydroxyl group, a —COOR 1  group, a (C 1 -C 3 )fluoroalkyl group, a (C 1 -C 3 )fluoroalkoxy group, a —NO2 group, a —NRiR2 group, a (C 1 -C 4 )alkoxy group, a phenoxy group and a (C 1 -C 3 )alkyl group, said alkyl being optionally mono-substituted by a hydroxyl group, n is 1, 2 or 3, n′ is 1 or 2, R′ is a hydrogen atom, a halogen atom or a group chosen among a (Ci-C3)alkyl group, a hydroxyl group, a —COOR 1  group, a —NO2 group, a —NR 1 R 2  group, a morpholinyl or a morpholino group, a N-methylpiperazinyl group, a (Ci-C3)fluoroalkyl group, a (C 1 -C 4 )alkoxy group and a —CN group, Z is N or C, Y is N or C, X is N or C, W is N or C, T is N or C, U is N or C, for use as an agent for preventing, inhibiting or treating pathological or nonpathological conditions linked with premature aging. Some of said compounds are new and also form part of the invention.

FIELD OF THE INVENTION

The present invention is generally dedicated to the use of compounds forthe manufacture of compositions useful to treat diseases related topremature aging. The compounds and compositions containing them andcompositions according to the invention may in particular be used toinhibit, prevent and/or treat Progeria.

BACKGROUND OF THE INVENTION

The present invention focuses on premature aging. Said premature agingmay be encountered in patients suffering from various diseases and inparticular from the Hutchinson-Gilford progeria syndrome (HGPS) and fromthe HIV infection.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorderphenotypically characterized by many features of premature aging. It isclinically characterized by postnatal growth retardation, midfacehypoplasia, micrognathia, premature atherosclerosis, absence ofsubcutaneous fat, alopecia and generalized osteodysplasia (Khalifa,1989-Hutchinson-Gilford progeria syndrome: report of a Libyan family andevidence of autosomal recessive inheritance. Clin. Genet. 35, 125-132.).At birth, the appearance of patients is generally normal, but by 1 yearof age patients show severe growth retardation, balding andsclerodermatous skin changes. They average about 1 m in height andusually weigh less than 15 kg even as teenagers. The age at death rangesfrom 7 to 28 years, with a median of 13.4 years. Over 80% of deaths aredue to heart attacks or congestive heart failure.

Premature aging syndrome has been observed in patients suffering fromHIV infections. One mechanical pathway underlying said premature agingcould be associated, as for the HGPS and as exposed beneath, with anaberrant splicing of the nuclear lamin A gene. Indeed it has recentlybeen hypothesized that protease inhibitors against HIV also block thetransformation of prelamin A into lamin A as it turned out in HGPS.

Most of the patients suffering from premature aging carry a heterozygoussilent mutation that activates the use of a cryptic 5′ splice site inexon 11 of LMNA pre-mRNA. This aberrant splicing event leads to theproduction of a truncated protein (progerin) with a dominant negativeeffect which is responsible for the observed phenotype (DeSandre-Giovannoli et al., 2003—Lamin A truncation in Hutchinson-Gilfordprogeria. Science 300, 2055/Pendas et al., 2002a—Defective prelamin Aprocessing and muscular and adipocyte alterations in Zmpste24metalloproteinase-deficient mice. Nat. Genet. 31, 94-99.).

Most of the premature aging syndromes in particular associated withHutchinson-Gilford progeria and HIV infection are due to a recurrent, denovo point mutation in LMNA exon 11: c.1824C>T. This mutation islocalized in the part of the gene specifically encoding lamin A (DeSandre-Giovannoli et al., 2003/De Sandre-Giovannoli and Levy,2006—Altered splicing in prelamin A-associated premature agingphenotypes. Prog. Mol. Subcell. Biol. 44, 199-232). Its predicted effectis a silent amino acid change at codon 608 (p.G608G). In fact, thissequence variation is not silent as it occurs in a probable exonsplicing enhancer. As a result, a cryptic splice site is activated intranscripts issued from the mutated allele, which is located 5nucleotides upstream of the mutation.

So far, therapeutic approaches have been mainly focused on progerinwhich is attached to a lipid anchor (a farnesyl lipid anchor). Thislipid anchor is attached to progerin by a specific cellular enzyme,protein farnesyltransferase. Experiments in mouse models suggest thatfarnesyltransferase inhibitors (FTIs) may have beneficial effects inhumans with progeria (Fong et al., 2006—A protein farnesyltransferaseinhibitor ameliorates disease in a mouse model of progeria. Science 311,1621-1623). More recently, Nicolas Levy's team has used a combination ofa statin and an aminobisphosphonate to prevent the fixation of the fattyacid to the progerin, and thus reduce its toxicity (Varela et al.,2008—Combined treatment with statins and aminobisphosphonates extendslongevity in a mouse model of human premature aging. Nat. Med. 14,767-772.).

In WO2006/081444 has been reported a method for reducing at least onecellular defect in a cell from a subject susceptible to a disease orcondition characterized by farnesylation on an abnormally farnesylatedform of a lamin, comprising administering to the cell a therapeuticallyeffective dose of farnesylstransferase inhibitor.

It has been recently reported in WO2008/003864 the use of ahydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor and afarnesyl-pyrophosphate synthase inhibitor, or one of their associatedphysiologically acceptable salts, in the preparation of a composition,for use in the treatment of human or animal, pathological ornonpathological situations related to the accumulation and/or thepersistence of prenylated proteins in cells, such as during progeria,restrictive dermopathy or physiological aging.

In WO 2008/115870 substituted quinoline are described, which are usefulfor treating cancer.

In US 2008/0161353 other substituted quinoline are disclosed as agentsto treat neurological conditions.

SUMMARY OF THE INVENTION

It has now been found that derivatives of formula (I) as defined informula (I) hereinafter are able to interfere with the usage of thecryptic splice and demonstrate efficient inhibition of aberrant splicingleading to progerin production as illustrated in the experimental dataherein after and, on the basis of such activity, the compounds areuseful in the treatment of premature aging and in particular ofprogeria.

The present invention therefore relates to compounds of formula (I) asdefined below for use as agents for preventing, inhibiting or treatingpathological or nonpathological conditions linked with premature aging.

The present invention moreover relates to a method of preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging, which comprises at least one step consisting inadministering to a patient suffering there from an effective amount of acompound as defined in formula (I) below or one of its pharmaceuticallyacceptable salts.

The present invention further relates to some particular derivatives assuch, as defined below.

The present invention also provides pharmaceutical compositionscomprising at least one of said particular compounds.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on a novel approach based on theinhibition of aberrant splicing leading to progerin production.

The truncated Lamin A protein lacking the last 150 base pairs of exon 11also called “progerin”, acting as a dominant negative mutant, ispredicted to be responsible for the characteristic manifestations seenin HGPS patients. Given that similar alteration of lamin A/C splicingwas observed in aged individuals, it is proposed here that therapeuticmolecules that interfere with the usage of the cryptic splice site willprevent side effects associated with accumulation of progerin duringphysiological aging. In other words, the compounds according to thepresent invention prevent usage of the cryptic 5′ splice site in exon 11of LMNA, allowing overcoming deleterious effect associated withprogerin.

According to a first aspect, a subject-matter of the present inventionrelates to a compound of formula (I)

wherein:

means an aromatic ring wherein V is C or N and when V is N, V is inortho, meta or para of Z, i.e. forms respectively a pyridazine, apyrimidine or a pyrazine group,

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a —CN group, a hydroxyl group, a —COOR₁ group, a(C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a —NO₂ group, a—NR₁R₂ group, a (C₁-C₄)alkoxy group, a phenoxy group and a (C₁-C₃)alkylgroup, said alkyl being optionally mono-substituted by a hydroxyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1, 2 or 3,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a morpholinyl or a morpholino group, a N-methylpiperazinyl group,a (C₁-C₃)fluoroalkyl group, a (C₁-C₄)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

Z is N or C,

Y is N or C,

X is Nor C,

W is N or C,

T is N or C,

U is N or C,

and wherein at most four of the groups V, T, U, Z, Y, X and W are N,

and at least one of the groups T, U, Y, X and W is N,

or anyone of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to a particular embodiment, the present invention furtherrelates to compounds of formula (I′)

wherein:

means an aromatic ring wherein V is C or N and when V is N, V is inortho, meta or para of Z, i.e. forms respectively a pyridazine, apyrimidine or a pyrazine group,

R independently represents a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a —COOH group, a(C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a —NO₂ group, a—NR₁R₂ group and a (C₁-C₃)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxy group, a —COOH group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

Z is N or C,

Y is N or C,

X is N or C,

W is N or C,

and wherein at most two of the groups V, Z, Y, X and W are N,

or anyone of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to one aspect of this particular embodiment, the presentinvention relates to a compound of formula (I′) as defined above,wherein V is N, for use as an agent for preventing, inhibiting ortreating pathological or nonpathological conditions linked withpremature aging.

According to one aspect of this particular embodiment, the presentinvention relates to a compound of formula (I′) as defined above,wherein Z is N, V is C, Y is N, X is C and W is C, for use as an agentfor preventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another aspect of this particular embodiment, the presentinvention relates to a compound of formula (I′) as defined above,wherein Z is C, V is C, Y is N, X is C and W is C, for use as an agentfor preventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another aspect of this particular embodiment, the presentinvention relates to a compound of formula (I′) as defined above,wherein Z is N, V is C, Y is C, X is N and W is C, for use as an agentfor preventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another aspect of this particular embodiment, the presentinvention relates to a compound of formula (I′) as defined above,wherein Z is N, V is C, Y is C, X is C and W is N, for use as an agentfor preventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to one aspect, the present invention relates to a compound offormula (I) as defined above, wherein Z is N, V is C, Y is N, X is C andW is C, for use as an agent for preventing, inhibiting or treatingpathological or nonpathological conditions linked with premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is C, Y is N, X is Cand W is C, for use as an agent for preventing, inhibiting or treatingpathological or nonpathological conditions linked with premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is C, X is Nand W is C, for use as an agent for preventing, inhibiting or treatingpathological or nonpathological conditions linked with premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is C, X is Cand W is N, for use as an agent for preventing, inhibiting or treatingpathological or nonpathological conditions linked with premature aging.

In one particular variant, the present invention is directed to acompound of formula (I) wherein:

Z is N or C, Y is N or C, X is N or C and W is C,

n is equal to 1,

R is a hydrogen atom, a —COOH group, a (C₁-C₃)alkyl group or a(C₁-C₃)fluoroalkoxy group,

R′ is a hydrogen atom,

R″ is a hydrogen atom, and

wherein at most two of the groups Z, Y and X are N,

or anyone of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

Still in another particular variant, the compound of formula (I) may bedefined as a compound of formula (IIa) as follows:

wherein:

Z is N or C, Y is N or C, X is N or C,

at least one of R₃ and R₄ is a hydrogen atom and the other is a —COOHgroup, a (C₁-C₃)alkyl group or a (C₁-C₃)fluoroalkoxy group, or anyone ofits pharmaceutically acceptable salt.

Therefore, the present invention extends to a compound of formula (IIa)as defined above for use as an agent for preventing, inhibiting ortreating pathological or nonpathological conditions linked withpremature aging.

The present invention further relates to a compound of formula (IIb)

wherein:

Y is N or C,

X is N or C,

R₅ is a hydrogen atom, a halogen atom or a group chosen among a(C₁-C₃)alkyl group, a —CN group, a (C₁-C₃)alkoxy group, a —NO₂ group anda (C₁-C₃)fluoroalkyl group, and

R′ and R″ are as defined above,

or anyone of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

The present invention further relates to a compound of formula (IIc)

-   -   wherein:

Y is N or C,

X is N or C,

R₅ is a hydrogen atom, a halogen atom or a group chosen among a(C₁-C₃)alkyl group, a —CN group, a (C₁-C₃)alkoxy group, a —NO₂ group anda (C₁-C₃)fluoroalkyl group, and

R′ and R″ are as defined above,

or anyone of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to a first particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ia-1)

-   -   wherein:

R independently represent a hydrogen atom, a halogen atom, or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a —COOH group, a(C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a —NO₂ group anda (C₁-C₃)alkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is 1 or 2, and advantageously 1, and

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxy group, a —COOH group and a —CN group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

The present invention further relates to a compound of formula (Ia-1) asdefined above, as such,

wherein:

R, R″ and n are as defined above,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a —COOH group and a —CN group, and

wherein R and R′ are not simultaneously a hydrogen atom or a methylgroup and R is not a bromine atom,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ia′-1)

wherein:

at least one of R₃ and R₄ is a hydrogen atom and the other is a hydrogenatom, a —COOH group or a (C₁-C₃)alkyl group, and

R″ is as defined above and is advantageously a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to a second particular embodiment, an additionalsubject-matter of the present invention is a compound of formula (Ib-1)

wherein:

R independently represent a hydrogen atom, a halogen atom, or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a —COOH group, a(C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a —NO₂ group, a—NR₁R₂ group and a (C₁-C₃)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group, nis 1 or 2, and advantageously 1,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxy group, a —COOH group and a —CN group, and

R″ is as defined above and is advantageously a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

The present invention further relates to a compound of formula (Ib-1) asdefined above, as such

wherein:

R′ and R″ are as defined above,

n is 1, and

R is a (C₁-C₃)fluoroalkoxy group,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ib′-1)

wherein:

at least one of R₃ and R₄ is a hydrogen atom and the other is a(C₁-C₃)fluoroalkoxy group or a (C₁-C₄)alkoxy group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to a third particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ic-1)

wherein:

R independently represent a hydrogen atom, a halogen atom, or a groupchosen among a (C₁-C₃)alkyl group a —CN group, a —COOH group, a(C₁-C₃)fluoroalkyl group, a —NO₂ group and a (C₁-C₃)alkoxy group,

n is 1 or 2, and advantageously 1,

R′ is a hydrogen atom or a (C₁-C₃)alkyl group, and in particular is ahydrogen atom, and

R″ is as defined above and is advantageously a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

The present invention further relates to a compound of formula (Ic-1) asdefined above, as such

wherein:

R, R′ R″ and n are as defined above, and

wherein R and R′ are not simultaneously a hydrogen atom,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ic′-1):

wherein:

at least one of R₃ and R₄ is a hydrogen atom and the other is a(C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to a fourth particular embodiment, an additionalsubject-matter of the present invention is a compound of formula (Id-1):

wherein:

R independently represent a hydrogen atom, a halogen atom, or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a —COOH group, a(C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group and a —NO₂ group,

n is 1 or 2, and advantageously 1,

R′ is a hydrogen atom or a (C₁-C₃)alkyl group, and in particular is ahydrogen atom, and

R″ is as defined above and is advantageously a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

The compound of formula (Id-1) as such and as defined above also formpart of the present invention, with the proviso that when R′ is ahydrogen atom, R is different from a —NO₂ group, or one of itspharmaceutically acceptable salt.

The compounds of formulae (I′), (IIa), (IIb), (IIc), (Ia-1), (Ib-1),(Ic-1) and (Id-1) can comprise one or more asymmetric carbon atoms. Theycan thus exist in the form of enantiomers or of diastereoisomers. Theseenantiomers, diastereoisomers and their mixtures, including the racemicmixtures, are encompassed within the scope of the present invention.

According to one aspect, the present invention relates to a compound offormula (I) as defined above, wherein Z is N, V is C, Y is N, X is C, Tis C, U is C and W is C, for use as an agent for preventing, inhibitingor treating pathological or nonpathological conditions linked withpremature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is C, Y is N, X is C,T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is C, X is N,T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is C, X is C,T is C, U is C and W is N, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is N and is in paraof Z, Y is N, X is C, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is N and is in paraof Z, Y is C, X is N, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is N and is in metaof Z and is in para of the bond linked to NR″, Y is N, X is C, T is C, Uis C and W is C, for use as an agent for preventing, inhibiting ortreating pathological or nonpathological conditions linked withpremature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is N and is in metaof Z and is in para of the bond linked to NR″, Y is C, X is N, T is C, Uis C and W is C, for use as an agent for preventing, inhibiting ortreating pathological or nonpathological conditions linked withpremature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is C, Y is C, X is N,T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is C, Y is N, X is N,T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is N and is in metaof Z and in ortho of the bond linked to NR″, Y is N, X is C, T is C, Uis C and W is C, for use as an agent for preventing, inhibiting ortreating pathological or nonpathological conditions linked withpremature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is N and is in paraof Z, Y is C, X is C, T is C, U is C and W is N, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is N and is in paraof Z, Y is C, X is N, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is N, X is N,T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is N and is in metaof Z and is in ortho of the bond linked to NR″, Y is N, X is N, T is C,U is C and W is C, for use as an agent for preventing, inhibiting ortreating pathological or nonpathological conditions linked withpremature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is C, Y is C, X is C,T is N, U is C and W is C, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is C, X is C,T is N, U is C and W is C, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is C, X is C,T is C, U is N and W is C, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

The compounds of the invention may exist in the form of free bases or ofaddition salts with pharmaceutically acceptable acids.

Suitable physiologically acceptable acid addition salts of compounds offormula (I) include hydrochloride, hydrobromide, tartrate, fumarate,citrate, trifluoroacetate, ascorbate, triflate, mesylate, tosylate,formate, acetate and malate.

The compounds of formula (I) and or salts thereof may form solvates(e.g. hydrates) and the invention includes all such solvates.

In the context of the present invention, the term:

-   -   “halogen” is understood to mean chlorine, fluorine, bromine, or        iodine, and in particular denotes chlorine, fluorine or bromine,    -   “(C₁-C₃)alkyl” as used herein respectively refers to C₁-C₃        normal, secondary or tertiary saturated hydrocarbon. Examples        are, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl,    -   “(C₁-C₃)alkoxy” as used herein respectively refers to        0-(C₁-C₃)alkyl moiety, wherein alkyl is as defined above.        Examples are, but are not limited to, methoxy, ethoxy,        1-propoxy, 2-propoxy,    -   “fluoroalkyl group” and “fluoroalkoxy group” refers respectively        to alkyl group and alkoxy group as above-defined, said groups        being substituted by at least one fluorine atom. Examples are        perfluoroalkyl groups, such as trifluoromethyl or        perfluoropropyl, and    -   “patient” may extend to humans or mammals, such as cats or dogs.

According to one embodiment, the present invention relates to a compoundof formula (I) as defined above for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging, wherein T is C, and Z, V, Y, X, U and W are asdefined above.

According to another embodiment, the present invention relates to acompound of formula (I) as defined above for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging, wherein W is C, and Z, V, Y, X,U and T are as defined above.

According to another embodiment, the present invention relates to acompound of formula (I) as defined above for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging, wherein Z is N, V is C, U is C,T is C and W, Y and X are as defined above.

According to one preferred aspect, the present invention relates to acompound of formula (I) as defined above, wherein Z is N, V is C, Y isN, X is C, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is C, V is C, Y isN, X is C, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is N, V is C, Y isC, X is N, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is N, V is C, Y isC, X is C, T is C, U is C and W is N, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is N, V is N andis in para of Z, Y is N, X is C, T is C, U is C and W is C, for use asan agent for preventing, inhibiting or treating pathological ornonpathological conditions linked with premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is C, Y is C, X is N,T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is C, V is C, Y isN, X is N, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is N, V is N andis in meta of Z and is in ortho of the bond linked to NR″, Y is N, X isC, T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is N, V is C, Y isN, X is N, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is N, V is N andis in meta of Z and is in ortho of the bond linked to NR″, Y is N, X isN, T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is N, V is C, Y isC, X is C, T is N, U is C and W is C, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to a particular embodiment, an additional subject-matter ofthe present invention is a compound of formula (Ia)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a —NO₂ group, a —NR₁R₂ groupand a (C₁-C₃)alkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom, a halogen atom or a group chosen among a(C₁-C₃)alkyl group, a —NO₂ group, a (C₁-C₃)alkoxy group and a —NR₁R₂group,

R₁ and R₂ are a hydrogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ib)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —NR₁R₂ group, a (C₁-C₃)fluoroalkoxygroup, a —NO₂ group, a phenoxy group and a (C₁-C₄)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is preferably 1 or 2,

n′ is as defined above and is preferably 1,

R′ is a hydrogen atom, a halogen atom or a group chosen among a(C₁-C₃)alkyl group and a (C₁-C₄)alkoxy group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ic)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)alkyl group, a (C₁-C₃)fluoroalkyl group, a —NR₁R₂ group, a —COOR₁group, a —NO₂ group and a (C₁-C₃)alkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Id)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)alkyl group, a (C₁-C₃)fluoroalkyl group and a (C₁-C₃)alkoxygroup,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ie)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom, a halogen atom or a group chosen among a(C₁-C₃)alkyl group and a (C₁-C₃)alkoxy group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (If)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ig)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom or a halogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ih)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (II)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ij)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ik)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom, a halogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Il)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Im)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Io)

wherein:

R independently represent a hydrogen atom or a halogen atom or a groupchosen among, a —NO₂ group, a —CN group and a (C₁-C₃)alkyl group, saidalkyl being optionally mono-substituted by a hydroxyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom, a halogen atom or a (C₁-C₃)fluoroalkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ip)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Iq)

wherein:

R independently represent a hydrogen atom, a (C₁-C₃)alkoxy group or a(C₁-C₃)fluoroalkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom or a group chosen among a —NR₁R₂ group, aN-methylpiperazinyl group, a (C₁-C₃)alkoxy group and a morpholino group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ir)

wherein:

R independently represent a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom or a group chosen among a —NR₁R₂ group, amorpholino group and a (C₁-C₃)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Iee)

wherein:

R independently represent a hydrogen atom, a (C₁-C₃)alkyl group or a(C₁-C₃)fluoroalkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 2,

R′ is a hydrogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

Among the previous defined families of compounds of formulae (Ia) to(Iee), some are more particularly preferred for their use as an agentfor preventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging. These preferred compoundsparticularly belong to formulae (Ia), (Ib), (Ic), (Id), (Ie), (Ii),(Ij), (Ik), (Io), (Ip) and (Ir), as defined above or one of itspharmaceutically acceptable salts.

Accordingly the present invention further relates to a compound chosenamong compounds of formulae (Ia), (Ib), (Ic), (Id), (Ie), (Ii), (Ij),(Ik), (Io), (Ip), (Ir) and their pharmaceutically acceptable salts foruse as an agent for preventing, inhibiting or treating pathological ornonpathological conditions linked with premature aging.

Furthermore, among such compounds particularly preferred for their useas described above, some of them, i.e. compounds of formulae (Ia), (Ib),(Ic), (Ie), (Ii), (Ij), (Ik), and (Io) are more particularly preferredfor their use, as described below:

Thus, according to a more particular embodiment, the present inventionparticularly focuses on a compound of formula (Ia)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a —COOR₁ group, a(C₁-C₃)fluoroalkyl group, a —NO₂ group and a (C₁-C₃)alkoxy group,

R₁ is a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above and more preferably is 1,

n′ is as defined above and more preferably is 1,

R′ is a hydrogen atom, a halogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

Still according to this more particular embodiment, the presentinvention more preferably focuses on compounds of formula (Ia′),

wherein,

R independently represent a hydrogen atom, a —COOR₁ group or a (C₁-C₃)alkyl group,

R₁ is as defined above,

R″ is a hydrogen atom,

n is 1 or 2,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another more particular embodiment, the present inventionparticularly focuses on a compound of formula (Ib)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a (C₁-C₃)fluoroalkoxy group and aphenoxy group,

R₁ is a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above and more preferably is 1,

n′ is as defined above,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another more particular embodiment, the present inventionparticularly focuses on a compound of formula (Ic)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)alkyl group, a —NO₂ group and a (C₁-C₃)alkoxy group,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above and more preferably is 1,

n′ is as defined above,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another more particular embodiment, the present inventionparticularly focuses on a compound of formula (Ie)

wherein:

R represents a hydrogen atom,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above and more preferably is 1,

n′ is as defined above,

R′ is a hydrogen atom or a halogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another more particular embodiment, the present inventionparticularly focuses on a compound of formula (II)

wherein:

R independently represent a hydrogen atom or a (C₁-C₃)alkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another more particular embodiment, the present inventionparticularly focuses on a compound of formula (Ij)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkyl group,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above and more preferably is 2,

n′ is as defined above,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another more particular embodiment, the present inventionparticularly focuses on a compound of formula (Ik)

wherein:

R represents a hydrogen atom,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above and more preferably is 1,

n′ is as defined above,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another more particular embodiment, the present inventionparticularly focuses on a compound of formula (Io)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)alkyl group and a —CN group,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above and more preferably is 1,

n′ is as defined above,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

In a particular embodiment, the present invention relates to a compoundof formula (Ib), (Ie) or (Ij) as defined above or one of itspharmaceutically acceptable salts, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to a preferred embodiment of the present invention, thecompound for use as an agent for preventing, inhibiting or treatingpathological or nonpathological conditions linked with premature aging,is chosen from:

-   (1) (8-Chloro-quinolin-2-yl)-pyridin-2-yl-amine-   (2) 2-(Quinolin-2-ylamino)-isonicotinic acid-   (3) (4-Methyl-pyridin-2-yl)-quinolin-2-yl-amine-   (4) Pyridin-2-yl-quinolin-2-yl-amine-   (5) 2-(8-Chloro-quinolin-2-ylamino)-isonicotinic acid-   (6) (8-Chloro-quinolin-2-yl)-(4-methyl-pyridin-2-yl)-amine-   (7) 6-(Quinolin-2-ylamino)-nicotinonitrile-   (8) Quinolin-2-yl-(4-trifluoromethoxy-phenyl)-amine-   (9) Pyridin-2-yl-quinolin-3-yl-amine-   (10) (3-Methoxy-pyridin-2-yl)-quinolin-3-yl-amine-   (11) Quinolin-3-yl-(5-trifluoromethyl-pyridin-2-yl)-amine-   (12) (5-Nitro-pyridin-2-yl)-quinolin-3-yl-amine,-   (13) (5-Methyl-pyridin-2-yl)-quinolin-3-yl-amine-   (14) 2-(Quinolin-3-ylamino)-isonicotinic acid-   (15) Quinolin-6-yl-(5-trifluoromethyl-pyridin-2-yl)-amine-   (16) (6-Methyl-pyridin-2-yl)-quinolin-6-yl-amine-   (17) N-(6-methylpyridin-2-yl)quinolin-2-amine-   (18) 8-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine-   (19) 4-methyl-N-(pyridin-2-yl)quinolin-2-amine-   (20) 4-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine-   (21) 3-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine-   (22) 3-methyl-N-(pyridin-2-yl)quinolin-2-amine-   (23) 6-((4-methylquinolin-2-yl)amino)nicotinonitrile-   (24) 6-((3-methylquinolin-2-yl)amino)nicotinonitrile-   (25) 6-chloro-N-(4-methylpyridin-2-yl)quinolin-2-amine-   (26) 6-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine-   (27) 4-methyl-N-(5-nitropyridin-2-yl)quinolin-2-amine-   (28) N-(3-nitropyridin-2-yl)quinolin-2-amine-   (29) 8-chloro-N-(3-nitropyridin-2-yl)quinolin-2-amine-   (30) 2-((4-methylquinolin-2-yl)amino)nicotinonitrile-   (31) N-(3-methylpyridin-2-yl)quinolin-2-amine-   (32) N-(5-methylpyridin-2-yl)quinolin-2-amine-   (33) 2-(quinolin-2-ylamino)isonicotinonitrile-   (34) N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine-   (35) 8-chloro-N-(3-methylpyridin-2-yl)quinolin-2-amine-   (36) 8-chloro-N-(5-methylpyridin-2-yl)quinolin-2-amine-   (37) 8-chloro-N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine-   (38) N-(3-methoxypyridin-2-yl)quinolin-2-amine-   (39) N-(5-nitropyridin-2-yl)quinolin-2-amine-   (40) 6-((8-chloroquinolin-2-yl)amino)nicotinonitrile-   (41) N-(5-fluoropyridin-2-yl)quinolin-2-amine-   (42) N-(6-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine-   (43) 8-chloro-N-(5-fluoropyridin-2-yl)quinolin-2-amine-   (44) 2-((8-chloroquinolin-2-yl)amino)nicotinic acid-   (45) 4-methyl-N-(6-methylpyridin-2-yl)quinolin-2-amine-   (46) 3-methyl-N-(6-methylpyridin-2-yl)quinolin-2-amine-   (47) 5-cyano-2-(quinolin-2-ylamino)pyridin-1-ium chloride-   (48) 2-((8-chloroquinolin-2-yl)amino)-4-methylpyridin-1-ium chloride-   (49) 8-chloro-N-(4-ethylpyridin-2-yl)quinolin-2-amine-   (50) 8-chloro-N-(6-ethylpyridin-2-yl)quinolin-2-amine-   (51) 8-chloro-N-(4,6-dimethylpyridin-2-yl)quinolin-2-amine-   (52) 6-((8-chloroquinolin-2-yl)amino)-2-methylnicotinonitrile-   (53) 8-chloro-N-(4-chloropyridin-2-yl)quinolin-2-amine-   (54) 8-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine-   (55) N-(5-bromo-4-methylpyridin-2-yl)-8-chloroquinolin-2-amine-   (56) 8-chloro-N-(3-ethyl-6-methylpyridin-2-yl)quinolin-2-amine-   (57) 8-fluoro-N-(4-methylpyridin-2-yl)quinolin-2-amine-   (58) 8-bromo-N-(4-methylpyridin-2-yl)quinolin-2-amine-   (59) methyl 6-(quinolin-2-ylamino)nicotinate-   (60) methyl 6-[(8-chloroquinolin-2-yl)amino]pyridine-3-carboxylate-   (61) methyl 6-[(3-methylquinolin-2-yl)amino]pyridine-3-carboxylate-   (62) methyl 2-[(8-chloroquinolin-2-yl)amino]pyridine-3-carboxylate-   (63) 8-methoxy-N-(4-methylpyridin-2-yl)quinolin-2-amine-   (64) N-(4-methylpyridin-2-yl)-5-nitroquinolin-2-amine-   (65) 2-N-(4-methylpyridin-2-yl)quinoline-2,8-diamine-   (66) 2-N-(4-methylpyridin-2-yl)quinoline-2,5-diamine-   (67) methyl 6-[(4-methylquinolin-2-yl)amino]pyridine-3-carboxylate-   (68) 8-chloro-N-[4-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine-   (69) 2-[(8-chloroquinolin-2-yl)amino]pyridin-3-ol-   (70) 8-chloro-N-[6-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine-   (71) 6-chloro-N-(5-fluoropyridin-2-yl)quinolin-2-amine-   (72) N-(6-ethylpyridin-2-yl)-3-methylquinolin-2-amine-   (73) N-(5-fluoropyridin-2-yl)-3-methylquinolin-2-amine-   (74) 3-methyl-N-[5-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine-   (75) 4-N-(8-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine-   (76) N-(4-methoxyphenyl)quinolin-2-amine-   (77) 8-chloro-N-(4-methoxyphenyl)quinolin-2-amine-   (78) 4-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine-   (79) N-(4-methoxyphenyl)-3-methylquinolin-2-amine-   (80) 3-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine-   (81) 1-N,1-N-dimethyl-4-N-(3-methylquinolin-2-yl)benzene-1,4-diamine-   (82) N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine-   (83) N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine-   (84) N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine-   (85) N-(4-nitrophenyl)quinolin-2-amine-   (86) N-(3-fluorophenyl)quinolin-2-amine-   (87) 8-chloro-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine-   (88) 8-chloro-N-(3-fluorophenyl)quinolin-2-amine-   (89) 2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride-   (90) 8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine-   (91)    3-methyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine-   (92) 3-methyl-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine-   (93) 3-methyl-N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine-   (94)    8-chloro-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine-   (95) 3-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium    chloride-   (96) 6-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine-   (97) 4-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium    chloride-   (98) 8-bromo-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine-   (99) 8-fluoro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine-   (100) 8-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine-   (101) N-(4-butoxyphenyl)-8-chloroquinolin-2-amine-   (102) N-(4-phenoxyphenyl)quinolin-2-amine-   (103) 8-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine-   (104)    8-chloro-N-[3-chloro-4-(trifluoromethoxy)phenyl]quinolin-2-amine-   (105) N-(6-methylpyridin-2-yl)quinolin-3-amine-   (106) N-(3-nitropyridin-2-yl)quinolin-3-amine-   (107) N-(5-methylpyridin-2-yl)quinolin-6-amine-   (108) N-(3-methoxypyridin-2-yl)quinolin-6-amine-   (109) 6-chloro-N-(pyrazin-2-yl)quinolin-2-amine-   (110) 8-bromo-N-(pyrazin-2-yl)quinolin-2-amine-   (111) 8-methyl-N-(pyrazin-2-yl)quinolin-2-amine-   (112) 8-chloro-N-(pyrazin-2-yl)quinolin-2-amine-   (113) N-(pyrazin-2-yl)quinolin-2-amine-   (114) 4-methyl-N-(pyrazin-2-yl)quinolin-2-amine-   (115) 3-methyl-N-(pyrazin-2-yl)quinolin-2-amine-   (116) 8-fluoro-N-(pyrazin-2-yl)quinolin-2-amine-   (117) 8-methoxy-N-(pyrazin-2-yl)quinolin-2-amine-   (118) N-(pyridin-3-yl)quinolin-3-amine-   (119) 8-chloro-N-(pyridin-4-yl)quinolin-2-amine-   (120) N-(pyridin-4-yl)quinolin-2-amine-   (121) N-(pyridin-4-yl)quinolin-3-amine-   (122) N-[4-(trifluoromethoxy)phenyl]quinolin-3-amine-   (123) N-(4-methoxyphenyl)quinolin-3-amine-   (124) N-[4-(trifluoromethoxy)phenyl]quinoxalin-2-amine-   (125) N-[2-methyl-4-(trifluoromethoxy)phenyl]quinoxalin-2-amine-   (126) N-[3-(trifluoromethoxy)phenyl]quinoxalin-2-amine-   (127) N-[2-(trifluoromethoxy)phenyl]quinoxalin-2-amine-   (128) N-(pyrimidin-2-yl)quinolin-2-amine-   (129) 8-chloro-N-(pyrimidin-2-yl)quinolin-2-amine-   (130) 4-methyl-N-(pyrimidin-2-yl)quinolin-2-amine-   (131) N-(pyrazin-2-yl)quinolin-6-amine-   (132) N-(pyrazin-2-yl)quinolin-3-amine-   (133) 6-methyl-N-(naphthalen-2-yl)pyridin-2-amine-   (134) N-(naphthalen-2-yl)pyridin-2-amine-   (135) N-(pyridin-2-yl)quinoxalin-2-amine-   (136) N-(4-methylpyridin-2-yl)quinoxalin-2-amine-   (137) 6-(quinoxalin-2-ylamino)pyridine-3-carbonitrile-   (138) N-(6-methylpyridin-2-yl)quinoxalin-2-amine-   (139) N-(4-methylpyridin-2-yl)-3-(trifluoromethyl)quinoxalin-2-amine-   (140) N-(3,5-dichloro-4-methylpyridin-2-yl)quinoxalin-2-amine-   (141) N-(4-methyl-3-nitropyridin-2-yl)quinoxalin-2-amine-   (142) N-(pyrimidin-2-yl)quinoxalin-2-amine-   (143)    4-N,4-N-dimethyl-7-N-[4-(trifluoromethoxy)phenyl]quinoline-4,7-diamine-   (144)    4-(morpholin-4-yl)-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine-   (145) 4-methoxy-N-(pyridin-2-yl)quinolin-7-amine-   (146) 4-methoxy-N-(4-methylpyridin-2-yl)quinolin-7-amine-   (147)    4-N,4-N-dimethyl-7-N-(4-methylpyridin-2-yl)quinoline-4,7-diamine-   (148) 5,8-dimethyl-N-(5-methylpyridin-2-yl)isoquinolin-6-amine-   (149) 5,8-dimethyl-N-(5-methylpyridin-2-yl)isoquinolin-6-amine-   (150) N-(4-methylpyridin-2-yl)-8-nitroquinolin-2-amine-   (151) 6-chloro-N-(6-ethylpyridin-2-yl)quinolin-2-amine-   (152) 6-chloro-N-(5-methylpyridin-2-yl)quinolin-2-amine-   (153) 6-chloro-N-[5-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine-   (154) N2-(8-chloroquinolin-2-yl)-4-methylpyridine-2,3-diamine-   (155) N-(4-butoxyphenyl)-3-methylquinolin-2-amine-   (156)    4-N-(6-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine-   (157) 8-chloro-N-(3-chloro-4-methoxyphenyl)quinolin-2-amine-   (158)    N1-(8-chloroquinolin-2-yl)-4-(trifluoromethoxy)benzene-1,2-diamine-   (159) 2-{4-[(8-chloroquinolin-2-yl)amino]phenoxy}ethan-1-ol-   (160) 6-chloro-N-(4-methylpyridin-2-yl)quinoxalin-2-amine-   (161) N-(4-ethylpyridin-2-yl)quinoxalin-2-amine-   (162) N-(5-bromo-4-methylpyridin-2-yl)quinoxalin-2-amine-   (163) N-(4,6-dimethylpyridin-2-yl)quinoxalin-2-amine-   (164) [2-(quinoxalin-2-ylamino)pyridin-4-yl]methanol-   (165) N-(4-methyl-5-nitropyridin-2-yl)quinoxalin-2-amine-   (166) N-(4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)quinolin-7-amine-   (167) 4-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine-   (168) N-(4-methylpyridin-2-yl)-4-(morpholin-4-yl)quinolin-7-amine    -   and their pharmaceutically acceptable salts.

Among said compounds, compounds (2), (3), (4), (5), (7), (8), (9), (10),(13), (15), (16), (17), (18), (25), (26), (28), (31), (32), (33), (34),(35), (36), (38), (39), (41), (42), (45), (59), (61), (82), (83), (86),(102), (105), (106), (107), (108), (109), (113), (120), (123), (125),(128), (135), (136), (137), (138), (142), (145), (146) and (147) are ofparticular interest.

The present invention therefore extends to compounds (2), (3), (4), (5),(7), (8), (9), (10), (13), (15), (16), (17), (18), (25), (26), (28),(31), (32), (33), (34), (35), (36), (38), (39), (41), (42), (45), (59),(61), (82), (83), (86), (102), (105), (106), (107), (108), (109), (113),(120), (123), (125), (128), (135), (136), (137), (138), (142), (145),(146) and (147) or one of its pharmaceutically acceptable salts for useas an agent for preventing, inhibiting or treating pathological ornonpathological conditions linked with premature aging.

Some of said preceding compounds are new and form part of the presentinvention: (2), (5), (7), (8), (10), (13), (15), (16), (18), (25), (26),(28), (31), (32), (33), (34), (35), (36), (38), (39), (41), (42), (59),(61), (82), (83), (86), (102), (105), (106), (107), (108), (109), (113),(125), (128), (135), (136), (137), (138), (142), (145), (146) and (147)or one of its pharmaceutically acceptable salts such as hydrochloride,hydrobromide, tartrate, fumarate, citrate, trifluoroacetate, ascorbate,triflate, mesylate, tosylate, formate, acetate and malate.

The compounds of formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), (Ij), (Ik), (Il), (Im), (Io), (Ip), (Iq), (Ir) and (Iee) cancomprise one or more asymmetric carbon atoms. They can thus exist in theform of enantiomers or of diastereoisomers. These enantiomers,diastereoisomers and their mixtures, including the racemic mixtures, areencompassed within the scope of the present invention.

Among the compounds of formula (I), some of them are new and form partof the invention, as well as their pharmaceutically acceptable salts,such as hydrochloride, hydrobromide, tartrate, fumarate, citrate,trifluoroacetate, ascorbate, triflate, mesylate, tosylate, formate,acetate and malate.

According to a particular embodiment, the present invention encompassescompounds of formula (Ig)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

n is 1 or 2,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

with the proviso that R and R′ are not simultaneously a hydrogen atom,

and when n and n′ are 1 and R is a hydrogen atom then R′ is not a —COOHgroup,

or anyone of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (If)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, and a (C₁-C3)alkoxy group,

n is 1 or 2,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

or anyone of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ih)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

n is 1 or 2,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

or anyone of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (II)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

n is 1 or 2,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

with the proviso that R and R′ are not simultaneously a hydrogen atom,

or anyone of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Im)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

n is 1 or 2,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

with the proviso that when n and n′ are 1 and R is a hydrogen atom, R′is not a chlorine atom,

or anyone of its pharmaceutically acceptable salt.

For a sake of simplification, the following compounds and theircorresponding definitions are called “new compounds”.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ia), as such,

wherein:

R″ and n are as defined in formula (Ia),

n′ is 1,

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a —NO₂ group, a(C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkoxy group,

R′ is a hydrogen atom or a halogen atom or a group chosen among a(C₁-C₃)alkyl group, a —COOR₁ group, and a —CN group,

R₁ is a hydrogen atom or a (C₁-C₃)alkyl group:

with the proviso that

when R and R′ are not simultaneously a hydrogen atom,

when n is 1, R is not a methyl group in ortho or para position withrespect to Z, Z being N,

when R′ is a hydrogen atom, R is not a bromine atom or a chlorine atom,

when R is a hydrogen atom, R′ is not a methyl or ethyl group, a —COOHgroup, a COOC₂H₅ group or a bromine atom, said bromine atom being inortho position of the bond linked to NR″,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ia), as such,

wherein:

R independently represent a hydrogen atom, a —NO₂ group, a(C₁-C₃)fluoroalkyl group, a (C₁-C₃)alkoxy group, a —CN group, a (C₁-C₃)alkyl group, a —COOR₁ group or a halogen atom,

R″ is as defined in formula (Ia),

R₁ is as defined above,

R′ is a hydrogen atom, a halogen atom or a (C₁-C₃) alkyl group,

n′ is 1,

n is 1 or 2,

with the proviso that

when n is 1, R is not a methyl group in ortho or para position withrespect to Z, Z being N,

R is not a bromine atom or a chlorine atom when R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore preferably focuses on compounds of formula (Ia′), as such,

wherein:

R independently represent a hydrogen atom, a —COOR₁ group, a (C₁-C₃)alkyl group, —NO₂ group, a (C₁-C₃)fluoroalkyl group, a —CN group, ahalogen atom or a hydroxyl group,

R₁ is as defined above,

R″ is as defined in formula (Ia),

n is 1 or 2,

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ib), as such,

wherein:

R′ and R″ are as defined in formula (Ib),

n is 1, and

R is a hydrogen atom or a (C₁-C₃)fluoroalkoxy group,

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ic), as such,

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a (C₁-C₃)fluoroalkyl group, a —CNgroup, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂ groupand a (C₁-C₃)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1 or 2, and advantageously 1,

n′ is 1 or 2,

R″ is as defined in formula (Ic),

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, a—NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group,

with the proviso that

R and R′ are not simultaneously a hydrogen atom,

R is not a bromine atom when R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ic), as such,

wherein:

R is a hydrogen atom, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)alkyl group,a (C₁-C₃)alkoxy group, a —NO₂ group or a —COOR₁ group,

n, R″, n′ and R₁ are as defined in formula (Ic),

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, a—NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group, and is preferablya hydrogen atom,

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Id), as such,

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group and a —NR₁R₂ group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1 or 2, and advantageously 1,

n′ is 1 or 2,

R″ is as defined in formula (I) and is advantageously a hydrogen atom,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, a—NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group,

with the proviso that when R′ is a hydrogen atom, R is different from a—NO₂ group, a —NH₂ group or a —COOH group,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Id), as such,wherein,

R is a hydrogen atom, a (C₁-C₃)alkyl group, a (C₁-C₃)alkoxy group or a(C₁-C₃)fluoro alkyl group,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group, and advantageously ahydrogen atom,

R″ is as defined in formula (I) and is advantageously a hydrogen atom,

n is 1 or 2, and advantageously 1,

n′ is 1 or 2,

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ie)

wherein:

R, R′, R″ n and n′ are as defined in formula (I),

with the proviso that

when R is a hydrogen atom, R′ is not a bromine atom,

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (II′), as such,

wherein:

R₃ is a (C₁-C₃)fluoroalkyl group or a (C₁-C₃)alkyl group,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n′ is as defined above and is advantageously 1,

with the proviso that

when R′ is a hydrogen atom, R₃ is not a methyl group or atrifluoromethyl group

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ij′), as such,

wherein:

R₄ is a (C₁-C₃)fluoroalkyl group or a (C₁-C₃)alkyl group,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n′ is as defined above and is advantageously 1,

with the proviso that

when R′ is a hydrogen atom, R₄ is not a methyl group

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ij″), as such,

wherein:

R₄ is a (C₁-C₃)fluoroalkyl group or a (C₁-C₃)alkyl group,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n′ is as defined above and is advantageously 1,

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ij′″), as such,

wherein:

R₄ is a (C₁-C₃)fluoroalkyl group or a (C₁-C₃)alkyl group,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —NO₂ group, a —NR₁R₂ group, a(C₁-C₃)alkoxy group and a —CN group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n′ is as defined above and is advantageously 1,

with the proviso that

when R′ is a chlorine atom or a hydrogen atom, R₄ is not an ethyl groupor a methyl group,

when R′ is a methyl group or a tertio-butyl group, R₄ is not a methylgroup,

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ik) as such,

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1 or 2, and is advantageously 1,

n′ is 1 or 2,

R″ is as defined in formula (Ik)

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ik), as such,

wherein:

R is a hydrogen atom,

R″ is as defined in formula (Ik),

R′ is a hydrogen atom, a halogen atom or a (C₁-C₃) alkyl group,

n is 1 or 2, and is advantageously 1,

n′ is 1 or 2,

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Io), as such,

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1, 2 or 3,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

with the proviso that

when R is a hydrogen atom and n′ is 1, R′ is not a hydroxyl group,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Io), as such,

wherein:

R is a hydrogen atom, a (C₁-C₃)alkyl group or a —CN group,

n is 1, 2 or 3,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group, and preferably is ahydrogen atom or a (C₁-C₃)alkyl group,

R₁ is as defined in formula (Io),

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ip), as such,

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1 or 2, and advantageously 1,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

with the proviso that

R and R′ are not simultaneously a hydrogen atom,

when n and n′ are 2 then R and R′ are not simultaneously a methyl group.

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ir), as such,

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1 or 2, and advantageously 1,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ir), as such,

wherein:

R is a hydrogen atom or a (C₁-C₃)alkyl group,

R′ is a (C₁-C₃)alkoxy group or a —NR₁R₂ group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

n and n′ are 1,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt.

Among said compounds as such, compounds (1), (2), (5)-(8), (10)-(16),(18), (21)-(44), (46)-(75), (77)-(84), (86)-(119), (121), (124)-(130),(132), (135)-(141), (143)-(147), (149)-(168) and their pharmaceuticallyacceptable salts are of particular interest.

The present invention therefore extends to compounds (1), (2), (5)-(8),(10)-(16), (18), (21)-(44), (46)-(75), (77)-(84), (86)-(119), (121),(124)-(130), (132), (135)-(141), (143)-(147), (149)-(168) and theirpharmaceutically acceptable salts, as such.

More preferably, compounds (1), (2), (5)-(7), (10)-(16), (18),(21)-(44), (46)-(74), (105)-(108), (124)-(130), (135)-(141),(145)-(147), (150)-(154), (159), (160)-(165), (168) and theirpharmaceutically acceptable salts are of particular interest.

The present invention therefore extends more preferably to compounds(1), (2), (5)-(7), (10)-(16), (18), (21)-(44), (46)-(74), (105)-(108),(124)-(130), (135)-(141), (145)-(147), (150)-(154), (159), (160)-(165),(168) and their pharmaceutically acceptable salts, such ashydrochloride, hydrobromide, tartrate, fumarate, citrate,trifluoroacetate, ascorbate, triflate, mesylate, tosylate, formate,acetate and malate.

Still more preferably, the present invention extends to compounds (2),(5), (7), (10), (13), (15), (16), (18), (25), (26), (28), (31)-(36),(38), (39), (41), (42), (59), (61), (105)-(108), (125), (128),(135)-(138), (145)-(147) and their pharmaceutically acceptable salts,such as hydrochloride, hydrobromide, tartrate, fumarate, citrate,trifluoroacetate, ascorbate, triflate, mesylate, tosylate, formate,acetate and malate.

The new compounds of the present invention, i.e. compounds of formula(Ia), (Ib), (Ic), (Id), (Ie), (Ik), (Ii′), (Ij′), (Ij″), (Ij′″), (Io),(Ip) and (Ir) and the specific compounds as listed above, are not onlyuseful as agent for inhibiting, preventing or treating premature agingbut can also be used as agent for inhibiting, preventing or treatingAIDS or cancer, and more particularly colorectal cancer, pancreaticcancer, lung cancer including non-small cell lung cancer, breast cancer,bladder cancer, gall bladder cancer, liver cancer, thyroid cancer,melanoma, uterine/cervical cancer, oesophageal cancer, kidney cancer,ovarian cancer, prostate cancer, head and neck cancer and stomachcancer, etc.

The compounds of the present invention can be prepared by conventionalmethods of organic synthesis practiced by those skilled in the art. Thegeneral reaction sequences outlined below represent a general methoduseful for preparing the compounds of the present invention and are notmeant to be limiting in scope or utility.

The compounds of general formula (I) can be prepared according to scheme1 below.

As appears in said scheme two routes are available for recovering acompound of formula (I) according to the present invention.

The synthesis is based on a coupling reaction alternatively startingfrom a halogeno-bicycle of formula (III), wherein X, Y, W, T, U, n′, R′and R″ are as defined above and X′ is a chlorine atom or a bromine atomor from a chloro-monocycle of formula (V), wherein Z, V, n and R are asdefined above and X′ is a chlorine atom or a bromine atom.

According to route (A), the compound of formula (III) is placed in aprotic solvent such as tert-butanol. The compound of formula (IV) isthen added in a molar ratio ranging from 1 to 1.5 with respect to thecompound of formula (III) in presence of an inorganic base, such asCs₂CO₃ or K₂CO₃ in a molar ratio ranging from 1 and 2, in the presenceof a diphosphine, such as Xantphos(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) or X-Phos(2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) in an amountranging from 2 mol % to 10 mol % relative to the total amount ofcompound of formula (III), and in the presence of a catalyst, such asPd(OAc)₂ or Pd₂ dba₃ in an amount ranging from 2 mol % to 10 mol %relative to the total amount of compound of formula (III). The reactionmixture can then be heated at a temperature ranging from 80 to 120° C.,for example at 90° C. and stirred for a time ranging form 15 to 25hours, for example during 20 hours under inert gas and for exampleargon. The reaction mixture can be concentrated under reduced pressure.

According to route (B) the compound of formula (V) is placed in a proticsolvent such as tert-butanol. The compound of formula (VI) is then addedin a molar ratio ranging from 1 to 1.5 with respect to the compound offormula (V) in presence of an inorganic base, such as Cs₂CO₃ or K₂CO₃ ina molar ratio ranging from 1 to 2, in the presence of a diphosphine,such as Xantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) orX-Phos (2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) in anamount ranging from 2 mol % to 10 mol % relative to the total amount ofcompound of formula (V), and in the presence of a catalyst, such asPd(OAc)₂ or Pd₂ dba₃ in an amount ranging from 2 mol % to 10 mol %relative to the total amount of compound of formula (V). The reactionmixture can then be heated at a temperature ranging from 80 to 120° C.,for example at 90° C. and stirred for a time ranging form 15 to 25hours, for example during 20 hours under inert gas and for exampleargon. The reaction mixture can be concentrated under reduced pressure.

The starting compounds of formula (III), (IV), (V) and (VI) arecommercially available or can be prepared according to methods known tothe person skilled in the art.

The chemical structures and spectroscopic data of some compounds offormula (I) of the invention are illustrated respectively in thefollowing Table I and Table II.

TABLE I (I)

Formula (Ia)

1

2

3

4

5

6

7

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

150

151

152

153

154 Formula (Ib)

8

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

155

156

157

158 Formula (Ic)

9

10

11

12

13

14

105

106

159 Formula (Id)

15

16

107

108 Formula (Ie)

109

110

111

112

113

114

115

116

117 Formula (If)

118 Formula (Ig)

119

120 Formula (Ih)

121 Formula (Ii)

122

123 Formula (Ij)

124

125

126

127 Formula (Ik)

128

129

130 Formula (Il)

131 Formula (Im)

132 Formula (Io)

135

136

137

138

139

140

141

160

161

162

163

164

165 Formula (Ip)

142 Formula (Iq)

143

144

166

167 Formula (Ir)

145

146

147

168 Formula (Iee)

148

149

TABLE II Ex Characterizations 1 MS (ESI) [M + H]⁺ = 256 2 ¹H NMR (300MHz, D₂O) δ 8.31 (d, J = 5.1, 1H), 8.21 (d, J = 9.3, 1H), 7.60 (d, J =7.5, 3H), 7.34 (dd, J = 6.2, 15.6, 2H), 7.18 (s, 1H), 6.99 (d, J = 9.1,1H) MS (ESI) [M + H]⁺ = 266 5 MS (ESI) [M + H]⁺ = 300 6 ¹H NMR (300 MHz,DMSO) δ 10.23 (s, 1H), 8.96 (s, 1H), 8.18 (d, J = 8.8, 2H), 7.78 (dd, J= 7.7, 13.7, 2H), 7.46 (d, J = 8.9, 1H), 7.31 (t, J = 7.8, 1H), 6.86 (d,J = 4.3, 1H), 2.37 (s, 3H). ¹³C NMR (75 MHz, DMSO) δ 153.63, 153.61,148.37, 147.32, 142.65, 137.52, 129.68, 129.47, 126.82, 125.06, 123.26,118.36, 115.10, 113.31, 21.24. MS (ESI) [M + H]⁺ = 270 7 ¹H NMR (300MHz, DMSO) δ 10.71 (s, 1H), 8.71 (d, J = 1.4, 1H), 8.62 (d, J = 8.9,1H), 8.24 (d, J = 8.9, 1H), 8.17 (dd, J = 1.9, 8.9, 1H), 7.89-7.74 (m,2H), 7.66 (dd, J = 7.9, 14.2, 2H), 7.42 (t, J = 7.3, 1H). ¹³C NMR (75MHz, DMSO) δ 156.09, 152.40, 152.11, 146.24, 141.07, 137.83, 129.87,127.67, 126.78, 124.50, 124.21, 118.04, 114.49, 111.67, 100.12. MS (ESI)[M + H]⁺ = 247 8 ¹H NMR (300 MHz, CDCl₃) δ 7.92 (d, J = 8.9, 1H), 7.79(d, J = 8.4, 1H), 7.65 (t, J = 7.7, 3H), 7.59 (dd, J = 7.1, 8.3, 1H),7.31 (t, J = 7.0, 1H), 7.20 (d, J = 8.5, 2H), 6.88 (d, J = 8.9, 1H),6.80 (s, 1H) ¹³C NMR (75 MHz, CDCl₃) δ 153.88, 147.62, 144.35, 139.26,138.11, 130.13, 127.65, 127.12, 124.43, 123.70, 122.20, 120.95, 112.25.MS (ESI) [M + H]⁺ = 305 10 ¹H NMR (300 MHz, CDCl₃) δ 9.10 (d, J = 2.5,1H), 8.83 (d, J = 2.6, 1H), 8.02 (d, J = 7.9, 1H), 7.94 (dd, J = 1.3,5.0, 1H), 7.85-7.79 (m, 1H), 7.52 (pd, J = 1.5, 6.9, 2H), 7.33 (s, 1H),7.04 (dd, J = 1.2, 7.9, 1H), 6.81 (dd, J = 5.1, 7.9, 1H), 3.95 (s, 3H)11 MS (ESI) [M + H]⁺ = 290 12 ¹H NMR (300 MHz, CDCl₃) δ 9.18 (d, J =2.7, 1H), 8.86 (d, J = 2.5, 1H), 8.56 (d, J = 2.3, 1H), 8.33 (dd, J =2.7, 9.2, 1H), 8.08 (d, J = 8.5, 1H), 7.83 (d, J = 8.5, 1H), 7.71-7.63(m, 2H), 7.57 (t, J = 7.4, 2H), 6.82 (d, J = 9.1, 1H) 13 ¹H NMR (300MHz, CDCl₃) δ 8.83 (d, J = 2.6, 1H), 8.37 (d, J = 2.3, 1H), 8.00 (d, J =8.2, 1H), 7.71 (d, J = 7.7, 1H), 7.59-7.51 (m, 1H), 7.46 (dd, J = 7.3,15.1, 2H), 6.71 (d, J = 8.3, 1H), 6.67 (d, J = 7.4, 1H), 2.49 (s, 3H)¹³C NMR (75 MHz, CDCl₃) δ 157.13, 154.59, 145.81, 144.43, 138.78,134.54, 129.22, 128.86, 127.41, 127.27, 121.48, 115.41, 106.50, 24.18.MS (ESI) [M + H]⁺ = 236 14 MS (ESI) [M + H]⁺ = 266 15 MS (ESI) [M + H]⁺= 290 16 ¹H NMR (300 MHz, CDCl₃) δ 8.77 (dd, J = 1.5, 4.2, 1H), 8.04(dd, J = 4.7, 8.7, 2H), 7.92 (d, J = 2.4, 1H), 7.59 (dd, J = 2.5, 9.1,1H), 7.47 (t, J = 7.8, 1H), 7.35 (dd, J = 4.2, 8.3, 1H), 6.87 (s, 1H),6.81 (d, J = 8.2, 1H), 6.70 (d, J = 7.4, 1H), 2.50 (s, 3H) MS (ESI) [M +H]⁺ = 236 18 ¹H NMR (300 MHz, CDCl₃) δ 8.53 (d, J = 59.9, 2H), 7.76 (d,J = 8.6, 1H), 7.58 (t, J = 8.3, 2H), 7.42 (d, J = 7.8, 1H), 7.09 (t, J =7.7, 1H), 6.95 (d, J = 8.7, 1H), 6.71 (d, J = 7.3, 1H), 2.38 (s, 3H) 21¹H NMR (300 MHz, CDCl₃) δ 8.78 (s, 1H), 8.13 (d, J = 5.1, 1H), 7.89 (d,J = 8.3, 1H), 7.79 (s, 1H), 7.63 (d, J = 8.0, 1H), 7.56 (d, J = 7.3,1H), 7.38 (s, 1H), 7.33 (t, J = 7.5, 1H), 6.79 (d, J = 4.9, 1H), 2.44(s, 6H) 22 ¹H NMR (300 MHz, CDCl₃) δ 8.95 (d, J = 8.4, 1H), 8.28 (d, J =5.7, 1H), 7.87 (d, J = 8.3, 1H), 7.78 (s, 1H), 7.76-7.70 (m, 1H), 7.62(d, J = 8.0, 1H), 7.60-7.52 (m, 1H), 7.42 (s, 1H), 7.32 (t, J = 7.4,1H), 6.95 (dd, J = 5.1, 6.5, 1H), 2.45 (s, 3H) 23 ¹H NMR (300 MHz,CDCl₃) δ 8.64 (d, J = 8.4, 1H), 8.55 (d, J = 2.1, 1H), 8.03 (s, 1H),7.90 (d, J = 8.5, 4H), 7.66 (t, J = 7.6, 1H), 7.44 (t, J = 7.6, 1H),7.06 (s, 1H), 2.67 (s, 4H) 24 ¹H NMR (300 MHz, CDCl₃) δ 9.09 (d, J =8.9, 1H), 8.53 (d, J = 1.7, 1H), 7.94 (dd, J = 2.2, 8.9, 1H), 7.92-7.84(m, 2H), 7.67 (d, J = 8.6, 2H), 7.65-7.58 (m, 1H), 7.40 (t, J = 7.4,1H), 2.49 (s, 3H) 25 ¹H NMR (300 MHz, CDCl₃) δ 8.16 (d, J = 5.2, 1H),8.10 (s, 1H), 7.90 (d, J = 8.8, 1H), 7.79 (d, J = 9.0, 1H), 7.66 (d, J =2.2, 1H), 7.55 (dd, J = 2.3, 8.9, 1H), 7.39 (d, J = 9.0, 1H), 6.79 (d, J= 5.2, 1H), 2.42 (s, 3H) MS (ESI) [M + H]⁺ = 270 26 ¹H NMR (300 MHz,CDCl₃) δ 8.06 (d, J = 8.3, 1H), 7.70 (d, J = 9.0, 1H), 7.64 (d, J = 8.9,1H), 7.49 (t, J = 7.9, 2H), 7.40 (dd, J = 2.3, 8.9, 1H), 7.18 (d, J =8.9, 1H), 6.68 (d, J = 7.4, 1H), 2.38 (s, 3H) MS (ESI) [M + H]⁺ = 270 27¹H NMR (300 MHz, CDCl₃) δ 9.17 (d, J = 2.5, 1H), 8.71 (s, 1H), 8.49 (dd,J = 2.6, 9.0, 1H), 7.99 (s, 1H), 7.93 (d, J = 8.9, 2H), 7.74-7.64 (m,1H), 7.48 (dd, J = 4.2, 11.4, 1H), 7.09 (s, 1H), 2.71 (s, 3H) 28 ¹H NMR(300 MHz, CDCl₃) δ 8.64-8.51 (m, 3H), 8.18 (d, J = 9.0, 1H), 7.93 (d, J= 8.4, 1H), 7.79 (d, J = 8.1, 1H), 7.73-7.64 (m, 1H), 7.51-7.41 (m, 1H),7.00 (dd, J = 4.6, 8.2, 1H), 6.75 (dd, J = 4.6, 8.3, 0H) 29 ¹H NMR (300MHz, CDCl₃) δ 10.77 (s, 1H), 8.60 (s, 3H), 8.19 (d, J = 8.2, 1H), 7.76(dd, J = 6.6, 25.5, 2H), 7.38 (d, J = 7.2, 1H), 7.04 (d, J = 4.4, 1H) 30¹H NMR (300 MHz, CDCl₃) δ 8.46 (dd, J = 1.9, 5.0, 1H), 7.87 (dd, J =2.0, 7.6, 1H), 7.82 (d, J = 7.3, 1H), 7.60 (t, J = 7.3, 2H), 7.43-7.33(m, 1H), 6.90 (dd, J = 5.0, 7.6, 1H), 2.64 (s, 3H) 31 ¹H NMR (300 MHz,CDCl₃) δ 8.44 (d, J = 9.1, 1H), 8.17 (d, J = 4.8, 1H), 8.03 (d, J = 9.1,1H), 7.78 (d, J = 8.4, 1H), 7.68 (d, J = 8.0, 1H), 7.62-7.54 (m, 1H),7.39 (d, J = 7.3, 1H), 7.32 (t, J = 7.5, 1H), 6.82 (dd, J = 5.0, 7.3,1H), 2.31 (s, 3H) MS (ESI) [M + H]⁺ = 236 32 ¹H NMR (300 MHz, CDCl₃) δ8.23 (d, J = 8.5, 1H), 8.10 (s, 1H), 7.91 (d, J = 8.9, 1H), 7.82 (d, J =8.4, 1H), 7.62 (d, J = 8.3, 1H), 7.56 (d, J = 7.3, 1H), 7.50 (dd, J =1.8, 8.5, 1H), 7.37-7.24 (m, 2H), 2.26 (s, 3H) MS (ESI) [M + H]⁺ = 23633 ¹H NMR (300 MHz, CDCl₃) δ 8.87 (s, 1H), 8.32 (d, J = 5.0, 1H), 7.95(d, J = 8.8, 1H), 7.84 (d, J = 8.3, 1H), 7.60 (dd, J = 7.4, 14.1, 2H),7.32 (t, J = 7.5, 1H), 7.04 (dd, J = 5.0, 9.0, 2H) MS (ESI) [M + H]⁺ =247 34 ¹H NMR (300 MHz, CDCl₃) δ 8.52 (s, 1H), 8.45 (d, J = 8.6, 1H),8.01 (d, J = 8.8, 1H), 7.87 (dd, J = 2.5, 8.5, 2H), 7.72-7.56 (m, 2H),7.39 (d, J = 9.0, 2H) MS (ESI) [M + H]⁺ = 290 35 ¹H NMR (300 MHz, CDCl₃)δ 8.32 (d, J = 9.1, 1H), 8.07 (d, J = 4.8, 1H), 7.93 (d, J = 9.1, 1H),7.59 (t, J = 7.9, 1H), 7.52 (d, J = 8.0, 1H), 7.36 (d, J = 7.2, 1H),7.14 (t, J = 7.8, 1H), 6.77 (dd, J = 5.0, 7.3, 1H), 2.29 (s, 3H) MS(ESI) [M + H]⁺ = 270 36 ¹H NMR (300 MHz, CDCl₃) δ 8.70 (d, J = 7.2, 1H),8.01 (s, 1H), 7.82 (d, J = 8.9, 1H), 7.62 (d, J = 7.6, 1H), 7.53 (dd, J= 1.8, 8.6, 1H), 7.46 (d, J = 7.9, 1H), 7.12 (t, J = 7.8, 1H), 7.05 (d,J = 8.8, 1H), 2.21 (s, 3H) MS (ESI) [M + H]⁺ = 270 37 ¹H NMR (300 MHz,CDCl₃) δ 9.08 (d, J = 8.5, 1H), 8.55 (s, 1H), 8.36 (s, 1H), 8.02 (d, J =8.1, 2H), 7.77 (d, J = 7.2, 1H), 7.62 (d, J = 7.6, 1H), 7.35-7.24 (m,1H), 7.12 (d, J = 8.8, 1H) MS (ESI) [M + H]⁺ = 324 38 ¹H NMR (300 MHz,CDCl₃) δ 8.69 (d, J = 9.1, 1H), 7.97 (d, J = 9.1, 1H), 7.80-7.74 (m,1H), 7.70 (d, J = 8.4, 1H), 7.59 (d, J = 8.0, 1H), 7.54-7.45 (m, 1H),7.22 (t, J = 7.5, 1H), 6.87 (d, J = 7.9, 1H), 6.68 (dd, J = 5.0, 7.9,1H), 3.73 (s, 3H) MS (ESI) [M + H]⁺ = 252 39 ¹H NMR (300 MHz, CDCl₃) δ8.57 (d, J = 29.4, 1H), 7.80 (d, J = 8.8, 1H), 7.66 (t, J = 6.7, 2H),7.46 (d, J = 7.9, 1H), 7.14 (t, J = 7.8, 1H), 7.06 (d, J = 8.8, 1H),6.79 (d, J = 7.3, 1H), 2.73 (dd, J = 7.6, 15.2, 2H), 1.28 (t, J = 7.7,3H) 40 ¹H NMR (300 MHz, DMSO) δ 9.75 (s, 1H), 9.12 (d, J = 2.3, 1H),8.50 (d, J = 2.2, 1H), 8.48 (s, 1H), 8.13 (s, 1H), 7.83 (s, 1H), 7.80(s, 1H), 7.64 (t, J = 7.7, 1H), 7.45 (t, J = 7.8, 1H) 41 ¹H NMR (300MHz, CDCl₃) δ 8.52 (dd, J = 2.8, 8.6, 1H), 8.35 (s, 1H), 8.15 (d, J =2.3, 1H), 7.94 (d, J = 8.8, 1H), 7.84 (d, J = 8.2, 1H), 7.65 (d, J =7.8, 1H), 7.59 (d, J = 7.2, 1H), 7.50-7.40 (m, 1H), 7.33 (t, J = 7.4,1H), 7.11 (d, J = 8.9, 1H) MS (ESI) [M + H]⁺ = 240 42 ¹H NMR (300 MHz,CDCl₃) δ 8.55 (d, J = 6.8, 1H), 8.01 (d, J = 8.9, 2H), 7.82 (dd, J =9.1, 17.3, 2H), 7.69 (d, J = 8.0, 1H), 7.63 (t, J = 7.6, 1H), 7.37 (t, J= 7.5, 1H), 7.32-7.18 (m, 2H) MS (ESI) [M + H]⁺ = 290 43 ¹H NMR (300MHz, DMSO) δ 10.41 (s, 1H), 9.08 (dd, J = 4.1, 9.3, 1H), 8.31 (d, J =2.9, 1H), 8.20 (d, J = 8.9, 1H), 7.88-7.70 (m, 3H), 7.44 (d, J = 8.9,1H), 7.32 (t, J = 7.8, 1H) ¹³C NMR (75 MHz, DMSO) δ 156.30, 153.32,153.04, 150.17, 142.55, 137.73, 135.06, 134.74, 129.58, 129.49, 126.86,125.29, 125.14, 125.04, 123.36, 114.91, 113.36. MS (ESI) [M + H]⁺ = 27444 ¹H NMR (300 MHz, CDCl₃) δ 11.09 (s, 1H), 8.78 (d, J = 9.0, 1H), 8.42(dd, J = 1.9, 4.7, 1H), 8.28 (dd, J = 1.9, 7.8, 1H), 8.11 (d, J = 9.1,1H), 7.73 (d, J = 7.5, 1H), 7.65 (d, J = 8.1, 1H), 7.27 (dd, J = 6.4,9.2, 1H), 6.88 (dd, J = 4.8, 7.8, 1H) MS (ESI) [M + H]⁺ = 300 46 ¹H NMR(300 MHz, CDCl₃) δ 8.59 (d, J = 8.3, 1H), 7.73 (d, J = 8.3, 1H), 7.57(s, 1H), 7.51 (t, J = 7.9, 1H), 7.43 (t, J = 9.2, 2H), 7.17 (t, J = 7.4,1H), 6.67 (d, J = 7.4, 1H), 2.36 (s, 3H), 2.28 (s, 3H) 47 ¹H NMR (300MHz, MeOD) δ 8.99 (s, 1H), 8.76 (d, J = 9.2, 1H), 8.32 (d, J = 8.7, 1H),8.22 (d, J = 8.6, 1H), 8.11 (d, J = 7.8, 1H), 8.01 (t, J = 7.1, 1H),7.76 (t, J = 7.4, 1H), 7.55-7.43 (m, 2H) MS (ESI) [M + H]⁺ = 247 48 ¹HNMR (300 MHz, MeOD) δ 8.48 (d, J = 9.1, 1H), 8.40 (d, J = 6.7, 1H), 7.94(d, J = 8.4, 1H), 7.90 (d, J = 7.8, 1H), 7.54 (t, J = 8.0, 1H), 7.38 (d,J = 8.6, 1H), 7.30 (s, 2H), 2.58 (s, 3H) MS (ESI) [M + H]⁺ = 270 49 ¹HNMR (300 MHz, CDCl₃) δ 9.34 (s, 1H), 8.95 (s, 1H), 8.21 (d, J = 5.1,1H), 7.87 (d, J = 8.9, 1H), 7.71 (d, J = 7.5, 1H), 7.52 (d, J = 7.9,1H), 7.19 (t, J = 7.8, 1H), 7.05 (d, J = 8.9, 1H), 6.84 (d, J = 5.1,1H), 2.76 (q, J = 7.6, 2H), 1.37 (t, J = 7.6, 3H) 50 ¹H NMR (300 MHz,CDCl₃) δ 8.57 (d, J = 29.4, 1H), 7.80 (d, J = 8.8, 1H), 7.66 (t, J =6.7, 2H), 7.46 (d, J = 7.9, 1H), 7.14 (t, J = 7.8, 1H), 7.06 (d, J =8.8, 1H), 6.79 (d, J = 7.3, 1H), 2.73 (dd, J = 7.6, 15.2, 2H), 1.28 (t,J = 7.7, 3H) 51 ¹H NMR (300 MHz, CDCl₃) δ 8.64 (s, 1H), 8.06 (s, 1H),7.89 (d, J = 8.7, 1H), 7.71 (d, J = 7.4, 1H), 7.54 (d, J = 7.8, 1H),7.20 (t, J = 7.7, 1H), 7.02 (d, J = 8.8, 1H), 6.67 (s, 1H), 2.43 (s,3H), 2.39 (s, 3H) ¹³C NMR (75 MHz, CDCl₃) δ 156.15, 153.17, 152.82,150.16, 143.70, 137.92, 131.34, 129.89, 126.49, 125.47, 123.43, 118.62,114.47, 111.02, 24.13, 21.70. MS (ESI) [M + H]⁺ = 284 52 ¹H NMR (300MHz, CDCl₃) δ 8.89 (d, J = 8.8, 1H), 8.05 (d, J = 8.8, 1H), 8.01 (s,1H), 7.93 (d, J = 8.8, 1H), 7.79 (d, J = 7.5, 1H), 7.64 (d, J = 8.0,1H), 7.32 (t, J = 7.8, 1H), 7.13 (d, J = 8.8, 1H), 2.67 (s, 3H) 53 ¹HNMR (300 MHz, CDCl₃) δ 9.27 (s, 1H), 8.33 (d, J = 5.7, 1H), 8.13 (d, J =5.2, 1H), 8.00 (d, J = 8.8, 1H), 7.76 (d, J = 7.4, 1H), 7.60 (d, J =8.0, 1H), 7.29 (d, J = 7.9, 1H), 7.07 (d, J = 8.9, 1H), 6.97 (d, J =4.8, 1H) 54 MS (ESI) [M + H]⁺ = 250 55 ¹H NMR (300 MHz, CDCl₃) δ 8.19(s, 1H), 7.90 (d, J = 9.0, 1H), 7.63 (d, J = 7.5, 1H), 7.52 (d, J = 7.9,1H), 7.33 (d, J = 7.4, 1H), 7.14 (t, J = 7.8, 1H), 6.69 (d, J = 7.5,1H), 2.70 (dd, J = 7.3, 14.8, 2H), 2.47 (s, 3H), 1.26 (t, J = 7.7, 3H)56 ¹H NMR (300 MHz, CDCl₃) δ 8.20 (s, 1H), 7.90 (d, J = 9.0, 1H), 7.63(d, J = 7.5, 1H), 7.52 (d, J = 7.9, 1H), 7.33 (d, J = 7.4, 1H), 7.14 (t,J = 7.8, 1H), 6.69 (d, J = 7.5, 1H), 2.70 (dd, J = 7.3, 14.8, 2H), 2.47(s, 3H), 1.25 (dd, J = 7.5, 15.5, 3H) 57 MS (ESI) [M + H]⁺ = 253 58 MS(ESI) [M + H]⁺ = 314-316 59 ¹H NMR (300 MHz, CDCl₃) δ 8.91 (d, J = 1.7,1H), 8.46 (d, J = 8.8, 1H), 8.28 (dd, J = 2.0, 8.8, 1H), 8.23 (s, 1H),8.03 (d, J = 8.8, 1H), 7.88 (d, J = 8.3, 1H), 7.70 (d, J = 8.0, 1H),7.67-7.58 (m, 1H), 7.38 (t, J = 7.4, 1H), 7.32 (d, J = 8.8, 2H), 3.91(s, 3H) 60 ¹H NMR (300 MHz, CDCl₃) δ 8.94 (d, J = 8.9, 1H), 8.91 (d, J =1.8, 1H), 8.37 (dd, J = 2.2, 8.8, 1H), 8.04 (d, J = 8.9, 2H), 7.77 (d, J= 7.5, 1H), 7.62 (d, J = 7.2, 1H), 7.30 (t, J = 7.8, 2H), 7.19 (d, J =8.8, 2H), 3.92 (s, 3H) 61 ¹H NMR (300 MHz, CDCl₃) δ 8.96 (d, J = 8.8,1H), 8.85 (d, J = 1.3, 1H), 8.28 (d, J = 9.9, 1H), 7.84 (d, J = 8.0,1H), 7.77 (s, 1H), 7.65 (s, 1H), 7.59 (d, J = 8.4, 2H), 7.53 (d, J =8.4, 1H), 7.31 (t, J = 7.4, 1H), 3.88 (s, 4H), 2.42 (s, 4H) MS (ESI)[M + H]⁺ = 294 62 ¹H NMR (300 MHz, CDCl₃) δ 11.02 (s, 1H), 8.75 (d, J =9.2, 1H), 8.44 (d, J = 3.7, 1H), 8.31 (d, J = 7.9, 1H), 8.10 (d, J =9.0, 1H), 7.72 (d, J = 7.5, 1H), 7.64 (d, J = 8.2, 1H), 7.27 (d, J =8.1, 1H), 6.88 (dd, J = 4.7, 7.8, 1H), 3.97 (s, 3H) MS (ESI) [M + H]⁺ =314 63 MS (ESI) [M + H]⁺ = 266 64 ¹H NMR (300 MHz, DMSO) δ 10.38 (s,1H), 8.56 (s, 1H), 8.28 (d, J = 9.1, 1H), 8.20-8.03 (m, 3H), 7.50 (d, J= 8.7, 1H), 7.45 (d, J = 8.0, 1H), 6.88 (d, J = 4.4, 1H), 2.37 (s, 3H)65 MS (ESI) [M + H]⁺ = 314-316 66 MS (ESI) [M + H]⁺ = 250 67 ¹H NMR (300MHz, DMSO) δ 10.51 (s, 1H), 8.83 (d, J = 2.3, 1H), 8.62 (d, J = 9.3,1H), 8.24 (dd, J = 2.7, 9.1, 1H), 7.96 (d, J = 8.9, 1H), 7.81 (d, J =7.8, 1H), 7.67 (t, J = 7.6, 1H), 7.45 (d, J = 11.2, 2H), 3.86 (s, 3H),2.62 (s, 3H) MS (ESI) [M + H]⁺ = 294 68 ¹H NMR (300 MHz, CDCl₃) δ 9.57(s, 1H), 8.44 (d, J = 4.8, 1H), 8.05 (d, J = 8.8, 1H), 7.86 (s, 1H),7.80 (d, J = 7.5, 1H), 7.64 (d, J = 8.0, 1H), 7.31 (t, J = 7.8, 1H),7.19 (d, J = 4.3, 1H), 7.04 (d, J = 8.8, 1H) 69 ¹H NMR (300 MHz, CDCl₃)δ 9.12 (s, 1H), 7.94 (d, J = 8.6, 1H), 7.71 (d, J = 7.5, 1H), 7.57 (d, J= 7.8, 1H), 7.40 (s, 1H), 7.25 (d, J = 10.2, 2H), 7.17 (s, 1H), 7.05 (s,1H) 70 ¹H NMR (300 MHz, CDCl₃) δ 9.07 (d, J = 8.5, 1H), 7.97 (d, J =8.8, 1H), 7.90 (t, J = 8.0, 1H), 7.84 (s, 1H), 7.75 (dd, J = 1.1, 7.5,1H), 7.62-7.55 (m, 1H), 7.31 (d, J = 7.6, 1H), 7.27 (t, J = 7.8, 1H),7.08 (d, J = 8.8, 1H) MS (ESI) [M + H]⁺ = 274 71 MS (ESI) [M + H]⁺ = 27472 ¹H NMR (300 MHz, CDCl₃) δ 8.67 (d, J = 7.9, 1H), 7.83 (d, J = 8.3,1H), 7.71 (s, 1H), 7.69-7.61 (m, 1H), 7.57 (d, J = 7.9, 2H), 7.52 (d, J= 7.1, 1H), 7.28 (t, J = 7.4, 1H), 2.74 (q, J = 7.6, 2H), 2.42 (s, 3H),1.31 (t, J = 7.6, 3H) MS (ESI) [M + H]⁺ = 264 73 ¹H NMR (300 MHz, CDCl₃)δ 8.91 (dd, J = 3.8, 9.0, 1H), 8.11 (d, J = 2.9, 1H), 7.81 (d, J = 8.3,1H), 7.71 (s, 1H), 7.56 (dd, J = 7.4, 14.1, 2H), 7.51-7.42 (m, 1H), 7.29(d, J = 7.2, 1H), 2.38 (s, 3H) MS (ESI) [M + H]⁺ = 254 74 ¹H NMR (300MHz, CDCl₃) δ 8.96 (d, J = 8.3, 1H), 8.49 (s, 1H), 7.89 (dd, J = 1.9,9.0, 1H), 7.82 (d, J = 8.2, 1H), 7.72 (s, 1H), 7.57 (t, J = 8.7, 3H),7.33 (t, J = 7.4, 1H), 2.37 (s, 3H) MS (ESI) [M + H]⁺ = 304 75 ¹H NMR(300 MHz, CDCl₃) δ 7.83 (d, J = 9.0, 1H), 7.69 (dd, J = 1.3, 7.6, 1H),7.53 (dd, J = 1.2, 8.0, 1H), 7.42 (d, J = 8.9, 2H), 7.15 (t, J = 7.8,1H), 6.89 (d, J = 8.9, 2H), 6.79 (d, J = 8.9, 2H), 2.97 (s, 6H) 77 ¹HNMR (300 MHz, CDCl₃) δ 7.83 (d, J = 8.8, 1H), 7.70 (d, J = 7.6, 1H),7.59 (d, J = 8.6, 2H), 7.52 (d, J = 7.3, 1H), 7.16 (t, J = 7.7, 1H),6.94 (d, J = 8.4, 3H), 6.86 (d, J = 8.8, 1H), 3.82 (s, 3H) ¹³C NMR (75MHz, CDCl₃) δ 156.40, 155.54, 144.29, 138.09, 132.96, 130.44, 129.99,126.61, 125.22, 123.29, 122.66, 114.73, 112.16, 55.74. MS (ESI) [M + H]⁺= 285 78 ¹H NMR (300 MHz, CDCl₃) δ 7.80 (t, J = 7.6, 2H), 7.64 (d, J =8.9, 2H), 7.61-7.55 (m, 1H), 7.33 (t, J = 7.6, 1H), 7.19 (d, J = 8.7,2H), 2.59 (s, 3H) 79 ¹H NMR (300 MHz, CDCl₃) δ 7.78 (d, J = 8.4, 1H),7.76-7.71 (m, 2H), 7.69 (s, 1H), 7.57 (dd, J = 1.1, 8.0, 1H), 7.51 (ddd,J = 1.5, 7.0, 8.4, 1H), 7.29-7.21 (m, 1H), 6.96-6.90 (m, 2H), 3.82 (s,3H), 2.35 (s, 3H) 80 ¹H NMR (300 MHz, CDCl₃) δ 7.92 (d, J = 8.9 Hz, 2H),7.84 (d, J = 8.3 Hz, 1H), 7.78 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.57(t, J = 7.7 Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 8.7 Hz, 2H),6.53 (s, 1H), 2.42 (s, 3H) ¹³C NMR (75 MHz, CDCl₃) δ 152.46, 146.25,143.86, 139.33, 136.83, 128.93, 126.96, 126.71, 124.75, 123.56, 121.88,120.44, 119.95, 17.77. MS (ESI) [M + H]⁺ = 319 81 ¹H NMR (300 MHz,CDCl₃) δ 7.75 (d, J = 8.3, 1H), 7.66 (d, J = 8.5, 3H), 7.55 (d, J = 7.8,1H), 7.48 (t, J = 7.6, 1H), 7.20 (d, J = 7.2, 1H), 6.80 (d, J = 8.8,2H), 6.32 (s, 1H), 2.93 (s, 7H), 2.35 (s, 3H) 82 ¹H NMR (300 MHz, CDCl₃)δ 7.92 (d, J = 8.9, 1H), 7.82-7.70 (m, 2H), 7.66 (d, J = 7.8, 1H), 7.59(t, J = 7.6, 1H), 7.30 (dd, J = 6.0, 13.5, 1H), 7.14 (s, 1H), 7.11 (s,1H), 6.84 (d, J = 8.9, 1H), 2.32 (s, 3H) MS (ESI) [M + H]⁺ = 319 83 ¹HNMR (300 MHz, CDCl₃) δ 7.93-7.86 (m, 1H), 7.85 (s, 1H), 7.82 (d, J =8.4, 1H), 7.59 (dd, J = 8.2, 15.5, 2H), 7.44-7.38 (m, 1H), 7.29 (dd, J =8.3, 16.8, 2H), 6.91 (d, J = 9.0, 1H), 6.87 (d, J = 8.3, 1H) MS (ESI)[M + H]⁺ = 305 84 ¹H NMR (300 MHz, CDCl₃) δ 8.67 (d, J = 8.1, 1H), 7.92(d, J = 8.9, 1H), 7.85 (d, J = 8.4, 1H), 7.63 (d, J = 7.6, 1H), 7.58 (d,J = 7.3, 1H), 7.30 (dd, J = 6.8, 14.8, 3H), 7.02 (t, J = 7.8, 1H), 6.89(d, J = 8.9, 1H) MS (ESI) [M + H]⁺ = 305 86 ¹H NMR (300 MHz, CDCl₃) δ7.93 (d, J = 8.9, 1H), 7.83 (d, J = 8.3, 1H), 7.70 (d, J = 12.0, 1H),7.61 (dd, J = 7.9, 18.1, 2H), 7.32 (d, J = 7.9, 1H), 7.31-7.25 (m, 1H),7.21 (t, J = 6.5, 1H), 6.92 (d, J = 8.9, 1H), 6.79-6.68 (m, 1H) MS (ESI)[M + H]⁺ = 239 87 ¹H NMR (300 MHz, CDCl₃) δ 8.27 (s, 1H), 7.76 (d, J =8.9, 1H), 7.67 (d, J = 7.5, 1H), 7.51 (d, J = 8.2, 1H), 7.45 (d, J =7.9, 1H), 7.28 (d, J = 8.2, 1H), 7.14 (t, J = 7.8, 1H), 6.86 (d, J =10.1, 1H), 6.76 (d, J = 8.9, 1H) MS (ESI) [M + H]⁺ = 339 88 ¹H NMR (300MHz, CDCl₃) δ 8.11 (dt, J = 2.1, 12.1, 1H), 7.76 (d, J = 8.9, 1H), 7.66(dd, J = 1.2, 7.6, 1H), 7.45 (dd, J = 1.1, 8.0, 1H), 7.22 (dd, J = 1.4,7.2, 2H), 7.18 (d, J = 7.6, 1H), 7.12 (d, J = 7.8, 1H), 6.75 (d, J =8.9, 1H), 6.69 (d, J = 7.9, 1H) MS (ESI) [M + H]⁺ = 273 89 ¹H NMR (300MHz, DMSO) δ 11.38 (s, 1H), 8.41 (d, J = 9.1, 1H), 7.93 (d, J = 7.8,1H), 7.80 (dt, J = 8.1, 20.9, 4H), 7.50 (d, J = 7.8, 3H), 7.36 (d, J =9.3, 1H) 90 ¹H NMR (300 MHz, CDCl₃) δ 7.84 (d, J = 9.1, 2H), 7.79 (d, J= 8.9, 1H), 7.67 (dd, J = 1.2, 7.6, 1H), 7.48 (dd, J = 1.1, 8.0, 1H),7.18 (s, 3H), 6.89 (s, 1H), 6.75 (d, J = 8.9, 1H) ¹³C NMR (75 MHz,CDCl₃) δ 153.88, 144.30, 143.91, 139.00, 138.25, 131.13, 130.13, 126.55,125.42, 123.45, 122.50, 122.17, 120.49, 119.10, 113.24. MS (ESI) [M +H]⁺ = 339 91 ¹H NMR (300 MHz, CDCl₃) δ 8.74 (s, 1H), 8.54 (s, 1H), 8.46(d, J = 8.8, 1H), 7.91 (dd, J = 5.5, 14.5, 2H), 7.79 (d, J = 8.9, 1H),7.67 (d, J = 2.1, 1H), 7.56 (dd, J = 2.3, 8.9, 1H), 7.35 (d, J = 8.9,1H) 92 ¹H NMR (300 MHz, CDCl₃) δ 8.67 (d, J = 7.9, 1H), 7.83 (d, J =8.3, 1H), 7.71 (s, 1H), 7.69-7.61 (m, 1H), 7.55 (dd, J = 7.5, 14.4, 2H),7.29 (d, J = 7.8, 1H), 6.80 (d, J = 7.4, 1H) 93 ¹H NMR (300 MHz, CDCl₃)δ 9.21 (dd, J = 1.5, 8.4, 1H), 7.85 (d, J = 8.4, 1H), 7.73 (s, 1H), 7.58(d, J = 7.8, 1H), 7.53 (dd, J = 1.3, 8.3, 1H), 7.40-7.35 (m, 1H), 7.32(dd, J = 1.1, 4.6, 1H), 7.31-7.24 (m, 2H), 7.04 (s, 1H), 7.02-6.94 (m,1H), 2.38 (s, 3H) 94 ¹H NMR (300 MHz, CDCl₃) δ 8.16 (d, J = 8.7, 1H),7.83 (d, J = 8.9, 1H), 7.63 (d, J = 7.6, 1H), 7.48 (d, J = 8.0, 1H),7.13 (t, J = 7.8, 1H), 7.08 (s, 1H), 7.04 (s, 2H), 6.81 (d, J = 8.9,2H), 2.27 (s, 3H) MS (ESI) [M + H]⁺ = 353 95 ¹H NMR (300 MHz, MeOD) δ8.42 (s, 1H), 7.94 (d, J = 7.9, 1H), 7.83 (d, J = 8.1, 1H), 7.78 (d, J =7.1, 1H), 7.72 (d, J = 8.7, 2H), 7.58 (d, J = 8.2, 3H), 2.60 (s, 3H) MS(ESI) [M + H]⁺ = 319 96 ¹H NMR (300 MHz, CDCl₃) δ 7.79 (d, J = 8.9, 1H),7.70 (d, J = 8.9, 1H), 7.64 (d, J = 8.9, 2H), 7.59 (d, J = 2.1, 1H),7.50 (dd, J = 2.3, 8.9, 1H), 7.19 (d, J = 8.6, 2H), 6.85 (d, J = 8.9,1H) MS (ESI) [M + H]⁺ = 281 97 ¹H NMR (300 MHz, MeOD) δ 8.11 (d, J =8.4, 1H), 7.81 (s, 2H), 7.62 (d, J = 8.7, 3H), 7.51 (d, J = 8.3, 2H),7.12 (s, 1H), 2.77 (s, 3H) MS (ESI) [M + H]⁺ = 319 98 MS (ESI) [M + H]⁺= 383-385 99 MS (ESI) [M + H]⁺ = 320 100 MS (ESI) [M + H]⁺ = 316 101 ¹HNMR (300 MHz, CDCl₃) δ 7.82 (d, J = 8.9, 1H), 7.70-7.63 (m, 1H), 7.51(dd, J = 5.3, 7.6, 3H), 7.14 (t, J = 7.8, 1H), 6.91 (d, J = 8.8, 3H),6.85 (d, J = 9.0, 2H), 3.96 (t, J = 6.5, 2H), 1.84-1.68 (m, 3H), 1.49(dd, J = 7.4, 15.0, 3H), 0.97 (t, J = 7.4, 3H) MS (ESI) [M + H]⁺ = 327102 ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J = 8.9, 1H), 7.76 (d, J = 8.5,1H), 7.63 (d, J = 8.1, 1H), 7.59 (s, 1H), 7.54 (d, J = 8.8, 2H),7.38-7.24 (m, 3H), 7.09 (d, J = 7.4, 1H), 7.02 (dd, J = 2.4, 8.8, 4H),6.90 (d, J = 8.9, 1H) MS (ESI) [M + H]⁺ = 313 103 MS (ESI) [M + H]⁺ =334 104 ¹H NMR (300 MHz, CDCl₃) δ 8.49 (d, J = 2.5, 1H), 7.89 (d, J =8.8, 1H), 7.72 (d, J = 7.6, 1H), 7.63 (dd, J = 2.5, 8.9, 1H), 7.53 (d, J= 8.0, 1H), 7.23 (dd, J = 6.2, 14.0, 2H), 7.04 (s, 1H), 6.81 (d, J =8.8, 1H) MS (ESI) [M + H]⁺ = 373 105 ¹H NMR (300 MHz, CDCl₃) δ 8.85 (d,J = 2.6, 1H), 8.45 (d, J = 2.3, 1H), 8.01 (d, J = 8.1, 1H), 7.71 (d, J =7.8, 1H), 7.58 (s, 1H), 7.53 (d, J = 7.6, 1H), 7.51-7.45 (m, 2H),7.45-7.36 (m, 1H), 6.72-6.62 (m, 2H), 2.48 (s, 3H) 13C NMR (75 MHz,CDCl₃) δ 157.18, 154.80, 145.42, 143.80, 138.17, 135.04, 128.88, 128.76,127.17, 127.04, 120.69, 115.22, 106.73, 24.38 106 ¹H NMR (300 MHz, DMSO)δ 10.24 (s, 1H), 9.06 (d, J = 2.3, 1H), 8.65 (d, J = 1.8, 1H), 8.60 (d,J = 8.3, 1H), 8.56 (d, J = 4.5, 1H), 7.97 (dd, J = 8.2, 14.4, 2H), 7.69(t, J = 6.9, 1H), 7.59 (t, J = 7.4, 1H), 7.08 (dd, J = 4.6, 8.3, 1H) MS(ESI) [M + H]⁺ = 267 107 ¹H NMR (300 MHz, CDCl₃) δ 8.77 (dd, J = 1.5,4.3, 1H), 8.06 (dd, J = 10.8, 18.4, 3H), 7.93 (d, J = 2.4, 1H), 7.57(dd, J = 2.4, 9.0, 1H), 7.39 (ddd, J = 3.1, 8.3, 12.5, 3H), 6.93 (d, J =8.4, 1H), 6.89 (s, 1H), 2.29 (s, 3H) 108 ¹H NMR (300 MHz, CDCl₃) δ 8.72(dd, J = 1.6, 4.2, 1H), 8.61 (d, J = 2.4, 1H), 8.11 (d, J = 8.3, 1H),8.00 (d, J = 9.0, 1H), 7.91 (dd, J = 1.2, 5.0, 1H), 7.69 (dd, J = 2.4,9.1, 1H), 7.35-7.26 (m, 2H), 7.01 (dd, J = 1.2, 7.9, 1H), 6.77 (dd, J =5.1, 7.8, 1H), 3.93 (s, 3H) 109 ¹H NMR (300 MHz, CDCl₃) δ 9.68 (s, 1H),8.21 (s, 2H), 7.94 (d, J = 8.9, 1H), 7.79 (d, J = 9.2, 1H), 7.67 (d, J =2.3, 1H), 7.56 (dd, J = 2.3, 8.9, 1H), 7.34 (d, J = 8.9, 1H) MS (ESI)[M + H]⁺ = 257 110 1H NMR (300 MHz, CDCl₃) δ 10.32 (s, 1H), 8.33-8.21(m, 2H), 8.05 (d, J = 8.9, 1H), 8.00 (dd, J = 1.2, 7.6, 1H), 7.69 (dd, J= 1.1, 7.8, 1H), 7.61 (s, 1H), 7.30-7.22 (m, 3H), 7.16 (d, J = 8.8, 1H).MS (ESI) [M + H]⁺ = 301-303 111 ¹H NMR (300 MHz, CDCl₃) δ 7.82 (d, J =8.9, 1H), 7.70-7.63 (m, 1H), 7.51 (dd, J = 5.3, 7.6, 3H), 7.14 (t, J =7.8, 1H), 6.91 (d, J = 8.8, 3H), 6.85 (d, J = 9.0, 2H), 3.96 (t, J =6.5, 2H), 1.84-1.68 (m, 3H), 1.49 (dd, J = 7.4, 15.0, 3H), 0.97 (t, J =7.4, 3H) 112 ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J = 8.9, 1H), 7.76 (d, J= 8.5, 1H), 7.63 (d, J = 8.1, 1H), 7.59 (s, 1H), 7.54 (d, J = 8.8, 2H),7.38-7.24 (m, 3H), 7.09 (d, J = 7.4, 1H), 7.02 (dd, J = 2.4, 8.8, 4H),6.90 (d, J = 8.9, 1H) ¹³C NMR (75 MHz, DMSO) δ 152.94, 150.19, 142.48,142.18, 138.20, 137.55, 135.74, 129.71, 126.99, 125.35, 123.84, 114.75.MS (ESI) [M + H]⁺ = 255 113 ¹H NMR (300 MHz, CDCl₃) δ 9.74 (s, 1H), 8.20(s, 2H), 8.03 (d, J = 8.6, 1H), 7.87 (d, J = 7.6, 1H), 7.80 (s, 1H),7.70 (d, J = 8.0, 1H), 7.63 (t, J = 7.7, 1H), 7.37 (t, J = 7.4, 1H),7.30 (d, J = 8.7, 1H) 114 ¹H NMR (300 MHz, CDCl₃) δ 9.67 (s, 1H),8.34-8.12 (m, 2H), 7.84 (d, J = 8.0, 2H), 7.70-7.54 (m, 1H), 7.38 (t, J= 7.6, 1H), 7.17 (s, 1H), 2.61 (s, 3H) MS (ESI) [M + H]⁺ = 237 115 ¹HNMR (300 MHz, CDCl₃) δ 10.15 (s, 1H), 8.24-8.12 (m, 2H), 7.79 (s, 1H),7.71 (s, 1H), 7.55 (t, J = 8.3, 2H), 7.30 (t, J = 7.9, 1H), 2.38 (s, 3H)MS (ESI) [M + H]⁺ = 237 116 MS (ESI) [M + H]⁺ = 240 117 MS (ESI) [M +H]⁺ = 253 118 MS (ESI) [M + H]⁺ = 222 119 MS (ESI) [M + H]⁺ = 256 121 MS(ESI) [M + H]⁺ = 222 124 ¹H NMR (300 MHz, CDCl₃) δ 8.42 (s, 1H), 7.95(dd, J = 1.3, 8.2, 1H), 7.87-7.78 (m, 3H), 7.70-7.61 (m, 1H), 7.55-7.47(m, 1H), 7.26 (dd, J = 2.4, 6.5, 3H), 6.90 (s, 1H) MS (ESI) [M + H]⁺ =306 125 ¹H NMR (300 MHz, CDCl₃) δ 8.42 (s, 1H), 8.03 (d, J = 9.5, 1H),7.92 (d, J = 8.2, 1H), 7.73 (d, J = 8.2, 1H), 7.61 (t, J = 7.3, 1H),7.46 (t, J = 7.2, 1H), 7.13 (s, 2H), 6.84 (s, 1H), 2.35 (s, 3H) 126 ¹HNMR (300 MHz, CDCl₃) δ 8.40 (s, 1H), 8.03 (s, 1H), 7.94 (d, J = 8.2,1H), 7.84 (d, J = 8.2, 1H), 7.65 (t, J = 7.4, 1H), 7.53 (d, J = 7.1,1H), 7.48 (d, J = 7.2, 1H), 7.35 (t, J = 8.2, 1H), 7.22 (s, 1H), 6.94(d, J = 8.1, 1H) 127 ¹H NMR (300 MHz, CDCl₃) δ 8.85 (dd, J = 1.0, 8.3,1H), 8.47 (s, 1H), 7.96 (d, J = 8.2, 1H), 7.85 (d, J = 8.3, 1H),7.72-7.61 (m, 1H), 7.57-7.47 (m, 1H), 7.42-7.36 (m, 1H), 7.33 (d, J =10.0, 1H), 7.14 (s, 1H), 7.13-7.04 (m, 1H) 128 ¹H NMR (300 MHz, CDCl₃) δ9.17 (s, 1H), 8.68 (d, J = 9.1, 1H), 8.64 (d, J = 4.8, 2H), 8.15 (d, J =9.1, 1H), 7.87 (d, J = 8.4, 1H), 7.76 (d, J = 8.1, 1H), 7.64 (t, J =7.7, 1H), 7.39 (t, J = 7.5, 1H), 6.87 (t, J = 4.8, 1H) ¹³C NMR (75 MHz,CDCl3) δ 158.34, 138.07, 129.85, 127.63, 127.31, 124.34, 114.20, 113.90.129 ¹H NMR (300 MHz, CDCl₃) δ 9.14 (s, 1H), 8.73 (d, J = 21.2, 3H), 8.17(s, 1H), 7.73 (d, J = 20.3, 2H), 7.28 (d, J = 9.6, 2H), 6.91 (s, 1H) 130¹H NMR (300 MHz, CDCl₃) δ 9.05 (s, 1H), 8.64 (d, J = 4.8, 2H), 8.52 (s,1H), 7.89 (dd, J = 8.5, 14.6, 2H), 7.63 (t, J = 7.5, 1H), 7.41 (t, J =7.4, 1H), 6.86 (t, J = 4.8, 1H), 2.74 (s, 3H) MS (ESI) [M + H]⁺ = 237132 ¹H NMR (300 MHz, CDCl₃) δ 8.86 (d, J = 2.6, 1H), 8.70 (d, J = 2.5,1H), 8.32 (d, J = 1.1, 1H), 8.25-8.21 (m, 1H), 8.10 (d, J = 2.7, 1H),8.06 (d, J = 8.3, 1H), 7.82 (dd, J = 1.2, 7.9, 1H), 7.66-7.51 (m, 3H),6.89 (s, 1H) 135 ¹H NMR (300 MHz, CDCl₃) δ 9.09 (s, 1H), 8.71 (s, 1H),8.54 (d, J = 8.4, 1H), 8.37 (dd, J = 1.0, 4.9, 1H), 7.96 (d, J = 8.2,1H), 7.85 (d, J = 8.3, 1H), 7.82-7.74 (m, 1H), 7.66 (t, J = 7.6, 1H),7.52 (dd, J = 7.0, 8.1, 1H), 7.02 (dd, J = 5.0, 7.2, 1H) MS (ESI) [M +H]⁺ = 223 136 ¹H NMR (300 MHz, CDCl₃) δ 9.02 (s, 1H), 8.70 (s, 1H), 8.30(s, 1H), 8.20 (d, J = 5.1, 1H), 7.94 (d, J = 8.1, 1H), 7.84 (d, J = 8.2,1H), 7.64 (t, J = 7.6, 1H), 7.49 (t, J = 8.1, 1H), 6.83 (d, J = 5.0,1H), 2.43 (s, 3H) ¹³C NMR (75 MHz, CDCl₃) δ 153.28, 150.20, 148.55,147.40, 140.93, 139.83, 138.35, 130.44, 129.16, 127.18, 126.28, 119.70,113.75, 21.87. MS (ESI) [M + H]⁺ = 237 137 ¹H NMR (300 MHz, DMSO) δ11.10 (s, 1H), 9.03 (s, 1H), 8.82-8.75 (m, 1H), 8.56 (d, J = 8.9, 1H),8.24 (dd, J = 2.3, 8.9, 1H), 7.96 (dd, J = 1.2, 8.2, 1H), 7.87 (dd, J =1.0, 8.3, 1H), 7.79-7.71 (m, 1H), 7.61 (ddd, J = 1.4, 7.0, 8.3, 1H) MS(ESI) [M + H]⁺ = 248 138 ¹H NMR (300 MHz, CDCl₃) δ 8.72 (s, 1H), 8.53(s, 1H), 8.20 (d, J = 8.3, 1H), 7.93 (d, J = 8.2, 1H), 7.81 (d, J = 8.3,1H), 7.62 (td, J = 3.4, 8.1, 2H), 7.53-7.43 (m, 1H), 6.83 (d, J = 7.4,1H), 2.48 (s, 3H) ¹³C NMR (75 MHz, CDCl₃) δ 156.86, 152.27, 148.40,140.92, 139.70, 139.00, 138.35, 130.42, 129.13, 127.14, 126.27, 117.76,110.01, 24.15. MS (ESI) [M + H]⁺ = 237 139 ¹H NMR (300 MHz, CDCl₃) δ8.53 (s, 1H), 8.20 (d, J = 4.8, 1H), 8.04 (d, J = 8.3, 1H), 7.92 (d, J =8.4, 1H), 7.87 (s, 1H), 7.79 (t, J = 7.6, 1H), 7.60 (t, J = 7.6, 1H),6.88 (d, J = 4.7, 1H), 2.46 (s, 3H) 140 ¹H NMR (300 MHz, CDCl₃) δ 9.93(s, 1H), 8.19 (s, 1H), 8.05 (d, J = 8.1, 1H), 7.99 (s, 1H), 7.82 (d, J =8.2, 1H), 7.69 (t, J = 7.6, 1H), 7.59 (t, J = 8.2, 1H), 2.53 (s, 4H) 141¹H NMR (300 MHz, CDCl₃) δ 9.72 (s, 1H), 9.35 (s, 1H), 8.30 (d, J = 5.0,1H), 8.05 (d, J = 7.7, 1H), 7.87 (d, J = 7.0, 1H), 7.66 (dd, J = 7.4,16.9, 3H), 6.92 (d, J = 4.9, 1H), 2.58 (s, 3H) 143 ¹H NMR (300 MHz,DMSO) δ 8.85 (s, 1H), 8.42 (d, J = 5.3, 1H), 7.96 (d, J = 9.1, 1H), 7.44(s, 1H), 7.30 (s, 4H), 7.28-7.21 (m, 2H), 6.66 (d, J = 5.3, 1H), 2.99(s, 6H) ¹³C NMR (75 MHz, DMSO) δ 156.82, 150.25, 149.69, 143.79, 141.71,125.95, 122.33, 118.88, 117.37, 115.95, 109.39, 104.92, 43.57 MS (ESI)[M + H]+ = 348 144 MS (ESI) [M + H]⁺ = 390 145 MS (ESI) [M + H]⁺ = 252146 ¹H NMR (300 MHz, DMSO) δ 9.34 (s, 1H), 8.59 (d, J = 5.2, 1H), 8.53(s, 1H), 8.13 (d, J = 5.1, 1H), 7.98 (d, J = 9.0, 1H), 7.66 (d, J = 9.1,1H), 6.80 (d, J = 5.2, 1H), 6.76 (s, 1H), 6.69 (d, J = 4.9, 1H), 4.00(s, 3H), 2.26 (s, 3H) ¹³C NMR (75 MHz, DMSO) δ 161.31, 155.67, 151.63,150.25, 147.77, 147.01, 142.97, 121.56, 119.16, 116.61, 114.75, 112.60,111.41, 98.91, 55.78, 20.66. MS (ESI) [M + H]⁺ = 266 147 MS (ESI) [M +H]⁺ = 279 149 MS (ESI) [M + H]⁺ = 318 150 MS (ESI) [M + H]⁺ = 280 151 ¹HNMR (300 MHz, CDCl₃) δ 8.35 (s, 1H), 8.04 (d, J = 8.3, 1H), 7.82 (d, J =8.9, 1H), 7.74 (d, J = 8.9, 1H), 7.60 (t, J = 7.8, 2H), 7.50 (dd, J =2.3, 8.9, 1H), 7.36 (d, J = 8.9, 1H), 6.79 (d, J = 7.4, 1H), 2.75 (q, J= 7.6, 2H), 1.30 (t, J = 7.6, 3H). MS (ESI) [M + H]⁺ = 284 152 ¹H NMR(300 MHz, CDCl₃) δ 8.30 (d, J = 8.5, 1H), 8.08 (s, 1H), 7.90 (d, J =9.0, 1H), 7.77 (d, J = 8.9, 1H), 7.65 (d, J = 2.2, 1H), 7.55 (td, J =2.0, 8.8, 2H), 7.39 (d, J = 9.0, 1H), 2.31 (s, 3H). MS (ESI) [M + H]⁺ =270 153 ¹H NMR (300 MHz, CDCl₃) δ 8.75 (s, 1H), 8.54 (s, 1H), 8.46 (d, J= 8.8, 1H), 7.91 (dd, J = 5.5, 14.5, 2H), 7.79 (d, J = 8.9, 1H), 7.67(d, J = 2.1, 1H), 7.56 (dd, J = 2.3, 8.9, 1H), 7.35 (d, J = 8.9, 1H). MS(ESI) [M + H]⁺ = 324 154 ¹H NMR (300 MHz, DMSO) δ 9.08 (s, 1H), 8.12 (d,J = 8.4, 1H), 7.73 (d, J = 8.2, 2H), 7.66 (d, J = 10.0, 1H), 7.53 (s,1H), 7.25 (s, 1H), 6.82 (s, 1H), 5.10 (s, 2H), 2.16 (s, 4H). MS (ESI)[M + H]⁺ = 285 155 ¹H NMR (300 MHz, CDCl₃) δ 7.68 (d, J = 8.3, 1H), 7.61(s, 1H), 7.56 (d, J = 11.5, 2H), 7.44 (d, J = 8.3, 1H), 7.38 (d, J =7.8, 1H), 7.13 (t, J = 7.4, 1H), 6.80 (d, J = 8.7, 2H), 3.85 (t, J =6.5, 2H), 2.18 (s, 3H), 1.73-1.58 (m, 2H), 1.48-1.31 (m, 2H), 0.88 (t, J= 7.3, 3H) MS (ESI) [M + H]⁺ = 307 156 ¹H NMR (300 MHz, CDCl₃) δ 7.75(d, J = 9.1, 1H), 7.62 (d, J = 8.9, 1H), 7.58 (d, J = 2.2, 1H), 7.48(dd, J = 2.4, 8.9, 1H), 7.30 (d, J = 8.9, 2H), 6.86 (d, J = 9.0, 1H),6.77 (d, J = 8.9, 2H), 6.71 (s, 1H), 2.97 (s, 6H) MS (ESI) [M + H]⁺ =298 157 ¹H NMR (300 MHz, CDCl₃) δ 7.98 (d, J = 2.6, 1H), 7.89 (d, J =8.9, 1H), 7.72 (d, J = 7.5, 1H), 7.62 (dd, J = 2.6, 8.8, 1H), 7.55 (d, J= 7.8, 1H), 7.20 (t, J = 7.8, 1H), 6.95 (d, J = 8.9, 1H), 6.84 (d, J =8.9, 1H), 6.79 (s, 1H), 3.91 (s, 3H) MS (ESI) [M + H]⁺ = 319 158 ¹H NMR(300 MHz, CDCl₃) δ 7.89 (d, J = 9.0, 1H), 7.70 (dd, J = 1.2, 7.5, 1H),7.56 (dd, J = 1.1, 8.0, 1H), 7.30 (d, J = 8.6, 1H), 7.20 (t, J = 7.8,1H), 6.71 (t, J = 5.9, 2H), 6.64 (d, J = 9.5, 1H). MS (ESI) [M + H]⁺ =354 159 ¹H NMR (300 MHz, CDCl₃) δ 8.80 (d, J = 2.6, 1H), 8.37 (d, J =2.6, 1H), 8.01 (d, J = 8.1, 1H), 7.91 (dd, J = 1.6, 4.9, 1H), 7.78-7.70(m, 1H), 7.58-7.43 (m, 2H), 7.09 (dd, J = 1.6, 7.6, 1H), 6.84 (dd, J =4.9, 7.6, 1H), 6.69 (s, 1H), 3.82-3.07 (m, 2H). 160 ¹H NMR (300 MHz,CDCl₃) δ 9.68-8.90 (m, 1H), 8.77 (s, 1H), 8.35 (s, 1H), 8.14 (d, J =5.0, 1H), 7.96 (s, 1H), 7.79 (d, J = 8.8, 1H), 7.61 (d, J = 8.5, 1H),6.88 (d, J = 4.8, 1H), 2.46 (s, 3H) 161 ¹H NMR (300 MHz, CDCl₃) δ 9.98(s, 1H), 8.70 (s, 1H), 8.45 (s, 1H), 8.27 (d, J = 5.2, 1H), 7.94 (d, J =8.1, 1H), 7.84 (d, J = 8.2, 1H), 7.63 (t, J = 7.5, 1H), 7.48 (t, J =7.5, 1H), 6.87 (d, J = 5.0, 1H), 2.74 (q, J = 7.6, 2H), 1.34 (t, J =7.6, 3H). MS (ESI) [M + H]⁺ = 251 162 ¹H NMR (300 MHz, CDCl₃) δ 8.73 (s,1H), 8.70-8.60 (m, 1H), 8.48 (s, 1H), 8.31 (s, 1H), 7.98 (d, J = 8.1,1H), 7.86 (d, J = 7.9, 1H), 7.68 (t, J = 8.2, 1H), 7.54 (t, J = 8.1,1H), 2.49 (s, 3H) MS (ESI) [M + H]⁺ = 315 163 ¹H NMR (300 MHz, CDCl₃) δ8.75 (s, 1H), 8.68 (s, 1H), 8.01 (s, 1H), 7.95 (d, J = 8.2, 1H), 7.84(d, J = 8.3, 1H), 7.64 (t, J = 8.2, 1H), 7.49 (t, J = 7.0, 1H), 6.69 (s,1H), 2.45 (s, 3H), 2.38 (s, 3H) MS (ESI) [M + H]⁺ = 251 164 ¹H NMR (300MHz, DMSO) δ 10.46 (s, 1H), 9.00 (s, 1H), 8.41 (s, 1H), 8.24 (d, J =3.0, 1H), 7.90 (d, J = 8.2, 1H), 7.79 (d, J = 8.3, 1H), 7.69 (t, J =7.0, 1H), 7.52 (t, J = 7.4, 1H), 6.98 (d, J = 4.8, 1H), 5.45 (q, J =5.6, 1H), 4.58 (d, J = 5.7, 2H). MS (ESI) [M + H]⁺ = 253 165 ¹H NMR (300MHz, CDCl₃) δ 9.07 (s, 1H), 8.79 (s, 1H), 8.51 (s, 1H), 8.18 (s, 1H),8.09-8.01 (m, 1H), 7.94 (d, J = 8.4, 1H), 7.81-7.71 (m, 1H), 7.69-7.59(m, 1H), 2.80 (s, 3H) MS (ESI) [M + H]⁺ = 282 166 ¹H NMR (300 MHz,CDCl₃) δ 8.49 (d, J = 5.0, 1H), 7.77 (d, J = 9.0, 1H), 7.32 (d, J = 2.0,1H), 7.12 (d, J = 9.0, 2H), 6.99 (dd, J = 2.0, J = 9.0, 1H), 6.82 (d, J= 9.0, 2H), 6.57 (d, J = 5.0, 1H), 5.78 (s, 1H), 3.74 (s, 3H), 3.17 (s,4H), 2.62 (s, 4H), 2.34 (s, 3H) 167 MS (ESI) [M + H]⁺ = 335 168 MS (ESI)[M + H]⁺ = 321

The following examples illustrate in detail the preparation of compounds(2), (3), (4), (7), (8), (26), (31), (82), (105), (113), (128), (135),(136), (137), (138), (142), (146), (13), (108), (16), (123), and (38)according to the invention. The structures of the products obtained havebeen confirmed by NMR spectra.

EXAMPLES

Typical Procedure for Pd-Catalysed Aminations

To a solution of 2-chloro quinoline (82 mg, 0.5 mmol, 1 equiv) intert-butanol (2 mL) were added the amino pyridine derivative/aniline(0.55 mmol, 1.1 equiv), Cs₂CO₃ (456 mg, 1.4 mmol, 2.8 equiv), Xantphos(5.8 mg, 0.01 mmol, 2 mol %), Pd(OAc)₂ (2.2 mg, 0.01 mmol, 2 mol %). Thereaction mixture was heated at 90° C. and stirred for 20 hours underargon. The reaction mixture was concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel to yieldcompounds (2), (3), (4) and (8).

Example 1 2-(Quinolin-2-ylamino)-isonicotinic acid (2) of Table I

¹H NMR (300 MHz, DMSO) δ 13.16 (s, 1H), 8.72 (d, J=5.2, 1H), 8.63 (d,J=9.0, 1H), 8.28-8.13 (m, 2H), 8.05 (d, J=8.0, 1H), 7.90 (t, J=7.5, 1H),7.74-7.67 (m, 2H), 7.67-7.59 (m, 2H).

MS (electrospray) m/z (%) 266.1 (100) [M+H]⁺.

Example 2 (4-Methyl-pyridin-2-yl)-quinolin-2-yl-amine (3) of Table I

¹H NMR (300 MHz, CDCl₃) δ 8.92 (s, 1H), 8.21 (d, J=5.3, 2H), 7.95 (d,J=8.9, 1H), 7.89 (d, J=8.4, 1H), 7.67 (d, J=8.0, 1H), 7.62 (t, J=7.7,1H), 7.40-7.28 (m, 2H), 6.78 (d, J=5.1, 1H), 2.41 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 154.3, 153.3, 149.5, 147.3, 137.7, 129.8,127.6, 127.1, 124.6, 123.7, 118.7, 114.1, 113.4, 21.7.

MS (electrospray) m/z (%) 236.2 (100) [M+H]⁺.

Example 3 Pyridin-2-yl-quinolin-2-yl-amine (4) of Table I

¹H NMR (300 MHz, CDCl₃) δ 8.38 (d, J=8.4, 1H), 8.31 (dd, J=1.0, 4.9,1H), 8.01 (d, J=8.9, 1H), 7.87 (d, J=8.4, 1H), 7.77-7.68 (m, 3H), 7.64(t, J=7.7, 1H), 7.36 (t, J=7.5, 1H), 7.31 (d, J=8.9, 1H), 6.94 (dd,J=5.0, 7.2, 1H).

¹³C NMR (75 MHz, CDCl₃) δ 154.1, 153.1, 147.8, 147.3, 138.3, 137.8,129.9, 127.6, 127.2, 124.6, 123.8, 117.4, 114.0, 113.0.

MS (electrospray) m/z (%) 222.2 (100) [M+H]⁺.

Example 4 Quinolin-2-yl-(4-trifluoromethoxy-phenyl)-amine (8) of Table I

¹H NMR (300 MHz, CDCl₃) δ 7.97 (d, J=8.8, 1H), 7.82 (d, J=8.4, 1H), 7.69(t, J=9.4, 3H), 7.62 (t, J=7.7, 1H), 7.34 (t, J=7.5, 1H), 7.23 (d,J=8.7, 2H), 6.92 (d, J=8.9, 1H), 6.74 (s, 1H).

¹³C NMR (75 MHz, CDCl₃) δ 153.9, 147.6, 144.4, 139.3, 138.1, 130.1,127.7, 127.1, 124.4, 123.7, 122.5, 122.2, 121.0, 119.1, 112.2.

MS (electrospray) m/z (%) 305.0 (100) [M+H]⁺.

According to route (A), the compound of formula (III) is placed in aprotic solvent such as tert-butanol. The compound of formula (IV) isthen added in a 1.1 molar ratio with respect to the compound of formula(III) in presence of an inorganic base, such as Cs₂CO₃ or K₂CO₃, in a2.8 molar ratio, in the presence of a diphosphine, such as Xantphos(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene), or X-Phos2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl in a 2 mol %amount relative to the total amount of compound of formula (III), and inthe presence of a catalyst, such as Pd(OAc)₂, or Pd₂ dba₃ in a 2 mol %amount relative to the total amount of compound of formula (III). Thereaction mixture is then heated at 90° C., and stirred during 20 hours,under argon. The reaction mixture is concentrated under reduced pressureand the resulting residue is diluted with ethyl acetate. The organicphase is then washed twice with water, dried on magnesium sulphate,filtered and concentrated under reduced pressure. The residue could thenbe purified by column chromatography on silica gel to yield purecompounds (7), (26), (31), (8), (82), (105), (113), (128), (135), (136),(137), (138), (142), (146).

According to route (B), the compound of formula (V) is placed in aprotic solvent such as tert-butanol. The compound of formula (VI) isthen added in a 1.1 molar ratio with respect to the compound of formula(V) in presence of Cs₂CO₃ in a 2.8 molar ratio, in the presence ofXantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) in a 2 mol %amount relative to the total amount of compound of formula (V), and inthe presence of a Pd(OAc)₂, in a 2 mol % amount relative to the totalamount of compound of formula (V). The reaction mixture is then heatedat 90° C., and stirred during 20 hours, under argon. The reactionmixture is concentrated under reduced pressure and the resulting residueis diluted with ethyl acetate. The organic phase is then washed twicewith water, dried on magnesium sulphate, filtered and concentrated underreduced pressure. The residue could then be purified by columnchromatography on silica gel to yield pure compound (13), (108), (16),(123), (38).

Example 5 Compound (7) of Table I

According to route (A), a mixture of 2-chloroquinoline (1.3 g),2-amino-5-cyanopyridine (1.1 g), Pd(OAc)₂ (36.5 mg), XantPhos (94 mg)and Cs₂CO₃ (7.4 g) in 32 mL of t-BuOH gave compound (7) (1.6 g).

Example 6 Compound (26) of Table I

According to route (A), a mixture of 2,6-dichloroquinoline (98.5 mg),6-amino-3-picoline (59.4 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg) andCs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (26) (92.3 mg).

Example 7 Compound (38) of Table I

According to route (B), a mixture of 2-aminoquinoline (79.2 mg),3-bromo-2-methoxypyridine (71.5 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8mg) and Cs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (38) (73.5 mg).

Example 8 Compound (31) of Table I

According to route (A), a mixture of 2-chloroquinoline (81.5 mg),2-amino-3-picoline (55 μL), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg) andCs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (31) (87.1 mg).

Example 9 Compound (8) of Table I

According to route (A), a mixture of 2-chloroquinoline (1.1 g),4-(trifluoromethoxy)aniline (1.0 mL), Pd(OAc)₂ (31.4 mg), XantPhos (80.9mg) and Cs₂CO₃ (6.4 g) in 28 mL of t-BuOH gave compound (8) (1.3 g).

Example 10 Compound (82) of Table I

According to route (A), a mixture of 2-chloroquinoline (81.5 mg),2-methyl-4-(trifluoromethoxy)aniline (81 μL), Pd(OAc)₂ (2.2 mg),XantPhos (5.8 mg) and Cs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound(82) (64 mg).

Example 11 Compound (13) of Table I

According to route (B), a mixture of 3-aminoquinoline (79 mg),2-bromo-5-methylpyridine (101 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg)and Cs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (13) (84.4 mg).

Example 12 Compound (105) of Table I

According to route (A), a mixture of 3-bromoquinoline (103.5 mg),6-amino-3-picoline (59.4 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg) andCs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (105) (66.5 mg).

Example 13 Compound (108) of Table I

According to route (B), a mixture of 6-aminoquinoline (79.0 mg),2-bromo-3-methoxypyridine (94.0 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8mg) and Cs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (108) (75.9 mg).

Example 14 Compound (16) of Table I

According to route (B), a mixture of 6-aminoquinoline (79.3 mg),2-bromo-6-methylpyridine, Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg) andCs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (16) (81.2 mg).

Example 15 Compound (113) of Table I

According to route (A), a mixture of 2-chloroquinoline (81.5 mg),aminopyrazine (52.3 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg) and Cs₂CO₃(456 mg) in 2 mL of t-BuOH gave compound (113) (60.7 mg).

Example 16 Compound (123) of Table I

According to route (B), a mixture of 3-bromoquinoline (103.5 mg),p-anisidine (67.7 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg) and Cs₂CO₃(456 mg) in 2 mL of t-BuOH gave compound (386) (65 mg).

¹H NMR (300 MHz, CDCl₃) δ 8.62 (d, J=2.8, 1H), 7.98 (d, J=7.4, 1H),7.61-7.54 (m, 1H), 7.45 (ddd, J=1.9, 4.9, 7.1, 3H), 7.18 (d, J=8.9, 2H),6.94 (d, J=8.9, 2H), 5.86 (s, 1H), 3.84 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 156.26, 144.27, 143.25, 139.18, 134.42,129.25, 129.18, 127.24, 126.40, 126.04, 123.03, 115.13, 114.26, 55.79.

Example 17 Compound (128) of Table I

According to route (A), a mixture of 2-chloroquinoline (81.5 mg),2-aminopyrimidine (52.3 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg) andCs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (128) (53.3 mg).

Example 18 Compound (135) of Table I

According to route (A), a mixture of 2-chloroquinoxaline (82.0 mg),2-aminopyridine (51.7 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg) andCs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (135) (47.7 mg).

Example 19 Compound (136) of Table I

According to route (A), a mixture of 2-chloroquinoxaline (82.0 mg),2-amino-3-methylpyridine (59.4 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg)and Cs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (136) (35.4 mg).

Example 20 Compound (137) of Table I

According to route (A), a mixture of 2-chloroquinoxaline (82.0 mg),2-amino-5-cyanopyridine (65.4 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg)and Cs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (137) (79.6 mg).

Example 21 Compound (138) of Table I

According to route (A), a mixture of 2-chloroquinoxaline (82.0 mg),6-amino-2-picoline (59.4 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg) andCs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (138) (89.4 mg).

Example 22 Compound (142) of Table I

According to route (A), a mixture of 2-chloroquinoxaline (82.0 mg),2-aminopyrimidine (52.3 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg) andCs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (142) (47.0 mg).

¹H NMR (300 MHz, CDCl₃) δ 10.07 (s, 1H), 8.57 (d, J=4.7, 2H), 8.04 (d,J=7.8, 1H), 7.83 (d, J=7.9, 1H), 7.68 (t, J=8.6, 1H), 7.58 (t, J=7.4,1H), 6.92 (t, J=4.6, 1H). MS (ESI) [M+H]+=224

Example 23 Compound (146) of Table I

According to route (A), a mixture of 4-methoxy-7-chloro-quinoline*(500.0 mg), 2-amino-4-methylpyridine (0.310 g) XPhos (123.0 mg), K₂CO₃(1.41 g) and Pd2 dba3 (118.0 mg) in 14 mL of t-BuOH gave compound 146(500 mg).

Preparation of 4-methoxy-7-chloro-quinoline

Into a 1-Neck round-bottom flask 4,7-dichloro-quinoline, (5.0 g, 0.025mol) was dissolved in 1.25 M of hydrogen chloride in methanol (16 mL).The mixture was heated to reflux overnight. After 16 hours of heating,the mixture was cooled to room temperature. The mixture was concentratedunder reduce pressure. The solid was dissolved in sodium bicarbonate (50mL, 0.6 mol) (saturated aqueous solution) and the solution was extractedwith Ethyl acetate (100 mL, 1 mol) (4×25 ml). The organic layer waswashed with sodium chloride (50 mL, 0.8 mol) (saturated aqueoussolution) (2×25 ml) and was dried over Na₂SO₄ and was concentrated underreduce pressure to give 4-methoxy-7-chloro-quinoline (4.5 g pale yellowpowder).

MS (ESI) [M+H]+=194

Example 24

Pharmacological Data

The compounds of the invention have been the subject of pharmacologicaltests which have demonstrated their relevance as active substances intherapy and in particular for preventing, inhibiting or treatingpathological or nonpathological conditions linked with premature aging.

The following materials and methods have been used.

Material and Methods

Minigene Constructs Reproduce Aberrant Splicing of LMNA mRNA, Leading toHGPS

In order to identify and characterize the factor(s) involved in the useof the cryptic 5′ splice site in exon 11 of LMNA, an ex vivo system hasbeen developed that recapitulates this splicing event. The cloning ofmutant and wild type constructs (FIG. 1A, for schematic representation)were carried out using a TOPO-TA cloning vector in which is inserted aminigene containing 142 nts of β-Globin first exon, 130 nts β-Globinfirst intron, 270 nts LMNA exon 11 either wild type or mutant, 322 ntsintron 11 and 46 nts exon 12. Using this system the splicing eventactivated by the GGC>GGT mutation in exon 11 of the LMNA gene wasconfirmed by transfections in cultured HeLa cells (FIG. 1B, lanes WT andMut) as well as in vitro splicing experiments using in vitro synthesizedradio labeled substrate (Panel C). Transfection experiments of minigeneconstructs containing or not the point mutation demonstrated that likein Progeria patients the mutation leads to a switch from the use of thenormal splice site (intron 11 position 1) to the use of the crypticsplice site upstream of the mutation (exon 11 position 1819) (FIG. 1,Panel C, compare lanes WT and Mut). Note that following a kinetics of invitro splicing for 150 minutes, aberrant splicing is observed with thewild type substrate (FIG. 1C, Lanes 1-7), implying that the mutation isnot a perquisite for cryptic splice site usage. The mutation simplyenhances the efficacy of selection of this cryptic splice site (FIG. 1C,Lanes 8-15).

Advantage has been taken of the luciferase system. The luciferase assayis an extremely sensitive and rapid assay. Linear results are seen overat least eight orders of magnitude of enzyme concentration. Moreover,the luciferase assay is well suited for high-throughput applications. Toconduct a Mid-throughput screening (MTS) for compounds repressing LMNAaberrant splicing, we have constructed a plasmid in which exon 11,intron 11 and part of exon 12 of LMNA gene were fused with luciferasecDNA (FIG. 2). Both wild type (WtLMNA-luc) and mutant (MutLMNA-luc)substrate harbouring exon 11 mutation have been constructed. In theseconstructs we have generated a single initiation codon in exon 11 suchas correct splicing will lead to luciferase expression, while aberrantsplicing will skip the initiation codon and thereby prevent luciferaseexpression. After transfection in HeLa cells, Luciferase assays (FIG.2B) and RT-PCR (FIG. 2C) indicate that WtLMNA-luc produces predominantlywild type splicing and large amount of luciferase activity, whereasMutLMNA-luc recapitulate the aberrant splicing profile with reducedluciferase expression (FIGS. 2 B and C, compare Wt and Mut). In order touse this system in MTS, we have generated a stable 293 cell linescontaining a single integrated copy of luciferase reporter containingLMNA mutation (MutLMNA-luc cell line) using the flp system fromINVITROGEN. This system allows us to perform a MTS for compounds able toenhance luciferase activity.

Plasmids constructs. LMNA sequences (1278 bp of exon 11, intron 11 and46 bp of exon 11) were PCR-amplified from either control or patient'scells genomic DNA with specific primer PCR fragments were purified withConcert Rapid PCR purification system (Invitrogen) and subcloned at theBamHI and EcoRI restriction sites of the pSpβm3S1 plasmid containing theβGlobin cassette (Labourier et al., 1999—Recognition of exonic splicingenhancer sequences by the Drosophila splicing repressor RSF1. NucleicAcids Res. 27, 2377-2386) to give the βGlo3S1LMNAwt and βGlo3S1LMNAmutconstructs. The chimeric βGlo-LMNA sequences were then inserted into thepcDNA3.1D/V5-His-TOPO vector (Invitrogen) to be used in transfection andin vitro splicing experiments. A single initiation codon ATG was kept inexon 11 of LMNA and LMNA sequences described above were fused at their3′ end to Fyrefly luciferase cDNA (LMNAlucWT) in order that removal ofintron 11 generates a transcript that encode a fusion protein harbouringluciferase activity, whereas usage of the cryptic splice site of mutatedexon 11 (LMNAlucMut) will remove the initiation codon preventingluciferase expression. Both sequences were cloned in pcDNA3 Flp-Invector (Invitrogen).

Transfection and RT-PCR.

HeLa cells transfections with splicing reporter constructs wereperformed with lipofectAMINE 2000 reagent (Invitrogen) according to themanufacturer's instructions. Twenty four hours after transfection, totalRNA was purified with RNA-PLUS™ (Quantum Bioprobe). First strand cDNAwas synthesized from 2 μg of RNA with the Amersham-Pharmacia Firststrand cDNA synthesis kit. For PCR analyses, 1/15 of the reaction wasamplified with Taq polymerase (Invitrogen). The cycle number was kept toa minimum to maintain linearity. PCR products were separated on a 1.5%agarose gel containing ethidium bromide and visualized under UV light.

A stable 293 cell line containing a single copy of LMNAlucMut minigenewas obtained using the Flp-In system from (Invitrogen) according tomanufacture procedure. Several clones were obtained and only one clonewas used to screen the whole chemical library (293FLP LMNA LUC cells#8).

Nuclear Extracts Preparation, Splicing and Complementation Assays.

HeLa cells nuclear extracts were prepared according to (Dignam et al.,1983—Eukaryotic gene transcription with purified components. MethodsEnzymol. 101, 582-598). Pre-mRNA were synthesized by in vitrotranscription in the presence of 20 units of T7 RNA polymerase,

1 μg of the suitable linearized plasmids and 5 μM [α-³²P] UTP (3000Ci/mmol) in 25 μl reactions according to manufacturer conditions. Invitro transcripts were quantified by Cerenkov counting. Splicingreactions were performed under standard conditions as describedpreviously (Tazi et al., 1986—A protein that specifically recognizes the3′ splice site of mammalian pre-mRNA introns is associated with a smallnuclear ribonucleoprotein. Cell 47, 755-766). Splicing products wereanalyzed by electrophoresis on 7% denaturing polyacrylamide gels andrevealed by autoradiography.

Material

293FLP LMNA LUC cells #8

Hygromycin B at 50 mg/mL (invitrogen 10687-010)

Dulbecco's Modified Eagle Medium (D-MEM) (1×)+GlutaMAX, liquid(invitrogen 31966-021)

Dulbecco's Phosphate Buffered Saline (D-PBS) (1×), liquid (invitrogen14190-169)

Trypsin 2.5%

Foetal calf serum (FCS)

Penicillin (P)

Streptomycin (S)

Passive Lysis Buffer (PLB) (5×) (Promega)

Bradford Reagent (B6916)

Luciferase assay buffer

96 Well Plate sterile, V-shape (greiner bio-one 651180)

96 Well Microplate sterile, flat bottom (greiner bio-one 655180)

96 Well Microplate, flat bottom, Chimney Well (greiner bio-one 655075)

CellTiter 96® AQ_(ueous) One Solution (Promega G3581)

Methods

First Day

Plate at 500 μM

In a 96 Well Plate sterile, V-shape one put 0.5 μl of drug compounds at50 mM and then add 49.5 μl of 10% DMSO.

Replica Plate

One pipets 47 μl of drug at 500 μM and adds 2004 of DMEM+Hygromycin B.At this stage the concentration of drug compound is 10 μM. One sharesout 100 μl in a 96 Well Microplate sterile, flat bottom (further calledluciferase plate) and 50 μl in other one (further called toxicityplate).

One washes 293FLP LMNA LUC cells once with D-PBS then adds 1 ml trypsinEDTA. Incubation at 37° C. for 2-3 minutes is proceeded. Then one adds 9ml DMEM (with 10% FCS, P/S).

One takes 7 μl of cell suspension and adds 144 blue trypan to countcells. Meanwhile cell suspension is centrifugated at 1200 rpm for 5minutes at room temperature (RT).

Cell concentration is brought at 105 cells per ml with DMEM+Hygromycin Bto have 104 cells per 100 μl.

Luciferase Plate

100 μl of suspension cells is added (at 104 cells per 100 μl) so finalconcentration of compounds is 5 μM.

Toxicity Plate

50 μl of suspension cells is added. The final concentration of compoundsis 5 μM.

48 Hours Later

Toxicity Plate

20 μl of CellTiter 96® AQueous One Solution is added per well.Incubation is proceeded at 37° C. for 2 h. Absorbance is red at 490 nm.

Luciferase Plate

Medium of the wells is gently removed then washed once by adding slowly150 μl of D-PBS 1×. D-PBS is removed. 40 μl of PLB 1× is added andincubated at RT for 30 minutes.

20 μl of cell lysate is put in a 96 Well Microplate, flat bottom,Chimney Well. 70 μl of luciferin assay substrate is added. One readluminescence for 1 second.

200 μl of Bradford reagent is added on the remaining cell lysate (20μl). Incubation is proceeded at RT for 30 min then one can readabsorbance at 595 nm. A range has to be made. Usually 5 differentconcentrations are tested: 0.25, 0.5, 0.75, 1 and 1.25 mg/ml.

Results

The compounds according to the present invention demonstrate an increaseof luciferase activity ranging between 3 and 7 fold compared to controluntreated MutLMNA-luc cell line.

In particular, the results are as follows for some of the compoundsaccording to the present invention.

Compound number Increase of luciferase activity 7 3.33 34 4.18 36 3.0631 5.07 26 6.20 8 3.35 105 3.25 135 4.58 136 5.20 137 4.64 138 8.22 1424.47 2 3.77 3 4.54 4 4.43 5 2.02 17 3.66 18 2.85 25 3.49 28 2.99 32 2.9633 2.14 35 2.74 38 5.81 39 4.29 41 3.32 42 3.87 45 3.08 59 2.49 61 2.0482 3.41 83 2.74 86 2.77 102 2.06 9 2.47 10 2.01 13 3.46 106 2.77 15 2.1716 4.56 107 2.20 108 4.57 109 2.79 113 2.28 120 2.38 123 2.94 125 2.59128 3.08 145 3.87 146 4.18 147 2.94

Therefore, the result of the tests carried out on the compoundsdisclosed in the present invention show that said compounds may beuseful to inhibit, prevent and/or treat diseases with premature agingand that are likely related to an aberrant splicing of the nuclear laminA gene. Among all, said disease may include Hutchinson Guilford ProgeriaSyndrome (HGPS), progeria, premature aging associated with HIVinfection, muscular dystrophy, Charcot-Marie-Tooth disorder, Wernersyndrome, but also atherosclerosis, insulin resistant type II diabetes,cataracts, osteoporosis and aging of the skin such as restrictivedermopathy.

For this purpose an effective amount of a said compound may beadministered to a patient suffering from premature aging and inparticular from progeria, and from the previous cited diseases.

The present invention is also related to the use of at least a compoundchosen among a compound of anyone of formula (I), (I′), (Ia), (Ib),(Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (Io),(Ip), (Iq), (Ir) or (Iee) as defined above, and compounds (1) to (168)as defined above, or one of its pharmaceutically acceptable saltsaccording to the present invention for the manufacture of apharmaceutical composition intended for the treatment of pathological ornonpathological conditions linked with premature aging and in particularprogeria.

The present invention also encompasses pharmaceutical compositionscomprising at least a compound chosen among new compounds of formula(Ia), (Ia′), (Ic), (Id), (Ii′), (Ij′), (Ij″), (Ij′″), (Ik), (Io), (Ip)and (Ir) as defined above and compounds (1), (2), (5)-(7), (10)-(16),(18), (21)-(44), (46)-(74), (105)-(108), (124)-(130), (135)-(141),(145)-(147), (150)-(154), (159), (160)-(165), (168), as defined above orany pharmaceutically acceptable salt thereof.

Thus, these pharmaceutical compositions contain an effective amount ofsaid compound, and one or more pharmaceutical excipients.

The aforementioned excipients are selected according to the dosage formand the desired mode of administration.

In this context they can be present in any pharmaceutical form which issuitable for enteral or parenteral administration, in association withappropriate excipients, for example in the form of plain or coatedtablets, hard gelatine, soft shell capsules and other capsules,suppositories, or drinkable, such as suspensions, syrups, or injectablesolutions or suspensions, in doses which enable the daily administrationof from 0.1 to 1000 mg of active substance.

The present invention is also related to the use of at least a compoundchosen among a compound of anyone of formula (I), (I′), (Ia), (Ib),(Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (Io),(Ip), (Iq), (Ir) or (Iee) as defined above, and compounds (1) to (168)as defined above, or one of its pharmaceutically acceptable saltsaccording to the present invention for the manufacture of apharmaceutical composition intended for inhibiting, preventing and/ortreating pathological or nonpathological conditions linked withpremature aging and in particular progeria but also all the previouslisted diseases.

The present invention further relates to a method of treatment ofpatients suffering form premature aging or anyone of the previous listeddisease, which comprises at least a step of administration to a patientsuffering thereof of an effective amount of a compound of anyone offormula (I), (I′), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii),(Ij), (Ik), (Il), (Im), (Io), (Ip), (Iq), (Ir), (Iee) and (1) to (168)or one of its pharmaceutically acceptable salts.

1. A method of preventing, inhibiting, or treating a pathological ornonpathological condition linked with premature aging, comprisingadministering to an individual at least one compound of formula (I):

wherein:

is an aromatic ring wherein V is C or N and when V is N, V is in anortho, meta or para position with respect to Z such that the ringrespectively forms a pyridazine, a pyrimidine, or a pyrazine, Rindependently represents a hydrogen atom, a halogen atom or a groupchosen among a —CN group, a hydroxyl group, a —COOR₁ group, a(C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a —NO₂ group, a—NR₁R₂ group, a (C₁-C₄)alkoxy group, a phenoxy group and a (C₁-C₃)alkylgroup, said alkyl group being optionally mono-substituted by a hydroxylgroup, R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkylgroup, n is 1, 2 or 3, n′ is 1 or 2, R′ is a hydrogen atom, a halogenatom or a group chosen among a (C₁-C₃)alkyl group, a hydroxyl group, a—COOR₁ group, a —NO₂ group, a —NR₁R₂ group, a morpholinyl or amorpholino group, a N-methylpiperazinyl group, a (C₁-C₃)fluoroalkylgroup, a (C₁-C₄)alkoxy group and a —CN group, R″ is a hydrogen atom or a(C₁-C₄)alkyl group, Z is N or C, Y is N or C, X is Nor C, W is N or C, Tis N or C, U is N or C, and wherein at most four of the groups V, T, U,Z, Y, X and W are N, and at least one of the groups T, U, Y, X and W isN, or a pharmaceutically acceptable salt thereof.
 2. The method of claim1, wherein Z is N, V is C, Y is N, X is C, T is C, U is C and W is C, Zis C, V is C, Y is N, X is C, T is C, U is C and W is C, Z is N, V is C,Y is C, X is N, T is C, U is C and W is C, Z is N, V is C, Y is C, X isC, T is C, U is C and W is N, Z is N, V is N and is in the para positionwith respect to Z, Y is N, X is C, T is C, U is C and W is C Z is C, Vis N and is in the para position with respect to Z, Y is C, X is N, T isC, U is C and W is C, Z is C, V is N and is in the meta position withrespect to Z and is in a para position with respect to the bond linkedto NR″, Y is N, X is C, T is C, U is C and W is C, Z is C, V is N and isin the meta position with respect to Z and is in the para position withrespect to the bond linked to NR″, Y is C, X is N, T is C, U is C and Wis C, Z is C, V is C, Y is C, X is N, T is C, U is C and W is C, Z is C,V is C, Y is N, X is N, T is C, U is C and W is C, Z is N, V is N and isin the meta position with respect to Z and in an ortho position withrespect to the bond linked to NR″, Y is N, X is C, T is C, U is C and Wis C, Z is N, V is N and is in the para position with respect to Z, Y isC, X is C, T is C, U is C and W is N, Z is N, V is N and is in the paraposition with respect to Z, Y is C, X is N, T is C, U is C and W is C, Zis N, V is C, Y is N, X is N, T is C, U is C and W is C, Z is N, V is Nand is in the meta position with respect to Z and is in the orthoposition with respect to of the bond linked to NR″, Y is N, X is N, T isC, U is C and W is C, Z is C, V is C, Y is C, X is C, T is N, U is C andW is C, Z is N, V is C, Y is C, X is C, T is N, U is C and W is C, or Zis N, V is C, Y is C, X is C, T is C, U is N and W is C.
 3. The methodof claim 1, wherein Z is N, V is C, Y is N, X is C, T is C, U is C and Wis C, Z is C, V is C, Y is N, X is C, T is C, U is C and W is C, Z is N,V is C, Y is C, X is N, T is C, U is C and W is C, Z is N, V is C, Y isC, X is C, T is C, U is C and W is N, Z is N, V is N and is in the paraposition with respect to Z, Y is N, X is C, T is C, U is C and W is C, Zis C, V is C, Y is C, X is N, T is C, U is C and W is C, Z is C, V is C,Y is N, X is N, T is C, U is C and W is C, Z is N, V is N and is in themeta position, with respect to Z and is in an ortho position withrespect to the bond linked to NR″, Y is N, X is C, T is C, U is C and Wis C, Z is N, V is C, Y is N, X is N, T is C, U is C and W is C, Z is N,V is N and is in the meta position with respect to Z and is in the orthoposition with respect to the bond linked to NR″, Y is N, X is N, T is C,U is C and W is C, or Z is N, V is C, Y is C, X is C, T is N, is C and Wis C.
 4. The method of claim 1, wherein the compound of formula (I) isselected from the group consisting of:

wherein: R independently represents a hydrogen atom, a halogen atom or agroup chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group,a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a —NO₂ group, a —NR₁R₂ groupand a (C₁-C₃)alkoxy group, R′ is a hydrogen atom, a halogen atom or agroup chosen among a (C₁-C₃)alkyl group, a —NO₂ group, a (C₁-C₃)alkoxygroup and a —NR₁R₂ group, R₁ and R₂ are a hydrogen atom or a(C₁-C₃)alkyl group,

wherein: R independently represents a hydrogen atom, a halogen atom or agroup chosen among a (C₁-C₃)alkyl group, a —NR₁R₂ group, a(C₁-C₃)fluoroalkoxy group, a —NO₂ group, a phenoxy group and a(C₁-C₄)alkoxy group, R₁ and R₂ are independently a hydrogen atom or a(C₁-C₃)alkyl group, R′ is a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group and a (C₁-C₄)alkoxy group,

wherein: R independently represents a hydrogen atom or a group chosenamong a (C₁-C₃)alkyl group, a (C₁-C₃)fluoroalkyl group, a —NR₁R₂ group,a —COOR₁ group, a —NO₂ group and a (C₁-C₃)alkoxy group, R′ is a hydrogenatom, R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkylgroup,

wherein: R independently represents a hydrogen atom or a group chosenamong a (C₁-C₃)alkyl group, a (C₁-C₃)fluoroalkyl group and a(C₁-C₃)alkoxy group, R′ is a hydrogen atom,

wherein: R is a hydrogen atom, R′ is a hydrogen atom, a halogen atom ora group chosen among a (C₁-C₃)alkyl group and a (C₁-C₃)alkoxy group,

wherein: R is a hydrogen atom, R′ is a hydrogen atom,

wherein: R is a hydrogen atom, R′ is a hydrogen atom or a halogen atom,

wherein: R is a hydrogen atom, R′ is a hydrogen atom,

wherein: R independently represents a hydrogen atom or a group chosenamong a (C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkoxy group, R′ is ahydrogen atom,

wherein: R independently represents a hydrogen atom or a group chosenamong a (C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkyl group, R′ is ahydrogen atom,

wherein: R is a hydrogen atom, R′ is a hydrogen atom, a halogen atom ora (C₁-C₃)alkyl group,

wherein: R is a hydrogen atom, R′ is a hydrogen atom,

wherein: R is a hydrogen atom, R′ is a hydrogen atom,

wherein: R independently represents a hydrogen atom, a halogen atom or agroup chosen among, a —NO₂ group, a —CN group and a (C₁-C₃)alkyl group,said alkyl being optionally mono-substituted by a hydroxyl group, R′ isa hydrogen atom, a halogen atom or a (C₁-C₃)fluoroalkyl group,

wherein: R is a hydrogen atom, R′ is a hydrogen atom,

wherein: R independently represents a hydrogen atom, a (C₁-C₃)alkoxygroup or a (C₁-C₃)fluoroalkoxy group, R″ is a hydrogen atom or a groupchosen among a —NR₁R₂ group, a N-methylpiperazinyl group, a(C₁-C₃)alkoxy group and a morpholino group, R₁ and R₂ are independentlya hydrogen atom or a (C₁-C₃)alkyl group,

wherein: R independently represents a hydrogen atom or a (C₁-C₃)alkylgroup, R″ is a hydrogen atom or a group chosen among a —NR₁R₂ group, amorpholino group and a (C₁-C₃)alkoxy group, R₁ and R₂ are independentlya hydrogen atom or a (C₁-C₃)alkyl group,

wherein: R independently represents a hydrogen atom, a (C₁-C₃)alkylgroup or a (C₁-C₃)fluoroalkyl group, R′ is a hydrogen atom or a(C₁-C₃)alkyl group, or (19) a pharmaceutically acceptable salt thereof.5. The method of claim 1, wherein the compound of formula (I) isselected from the group consisting of

wherein: R independently represents a hydrogen atom, a halogen atom or agroup chosen among a (C₁-C₃)alkyl group, a —CN group, a —COOR₁ group, a(C₁-C₃)fluoroalkyl group, a —NO₂ group and a (C₁-C₃)alkoxy group, R₁ isa hydrogen atom or a (C₁-C₃)alkyl group, R′ is a hydrogen atom, ahalogen atom or a (C₁-C₃)alkyl group,

wherein: R independently represents a hydrogen atom, a halogen atom or agroup chosen among a (C₁-C₃)alkyl group, a (C₁-C₃)fluoroalkoxy group anda phenoxy group, R₁ is a hydrogen atom or a (C₁-C₃)alkyl group, R′ is ahydrogen atom,

wherein: R independently represents a hydrogen atom or a group chosenamong a (C₁-C₃)alkyl group, a —NO₂ group and a (C₁-C₃)alkoxy group, R′is a hydrogen atom,

wherein: R is a hydrogen atom, R′ is a hydrogen atom or a halogen atom,

wherein: R independently represents a hydrogen atom or a (C₁-C₃)alkoxygroup, R′ is a hydrogen atom,

wherein: R independently represents a hydrogen atom or a group chosenamong a (C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkyl group, R′ is ahydrogen atom,

wherein: R is a hydrogen atom, R′ is a hydrogen atom,

wherein: R independently represents a hydrogen atom or a group chosenamong a (C₁-C₃)alkyl group and a —CN group, R′ is a hydrogen atom, or(9) a pharmaceutically acceptable salt thereof.
 6. The method of claim1, wherein the compound of formula (I) is selected from the groupconsisting of: (1) the compound of formula (Ia)

wherein: n′ is 1, R independently represents a hydrogen atom, a halogenatom or a group chosen among a (C₁-C₃)alkyl group, a —CN group, ahydroxyl group, a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a —NO₂group, a (C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkoxy group, R′ is ahydrogen atom, a halogen atom or a group chosen among a (C₁-C₃)alkylgroup, a —COOR₁ group, and a —CN group, R₁ is a hydrogen atom or a(C₁-C₃)alkyl group with the proviso that R and R′ are not simultaneouslya hydrogen atom, when n is 1, R is not a methyl group in the ortho orpara position with respect to Z, Z being N, when R′ is a hydrogen atom,R is not a bromine atom or a chlorine atom, when R is a hydrogen atom,R′ is not a methyl or ethyl group, a —COON group, a COOC₂H₅ group or abromine atom, said bromine atom being in an ortho position with respectto the bond linked to NR″; (2) the compound of formula (Ic)

wherein: R independently represents a hydrogen atom, a halogen atom or agroup chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group,a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a —NO₂ group, a —NR₁R₂ groupand a (C₁-C₃)alkoxy group, R₁ and R₂ are independently a hydrogen atomor a (C₁-C₃)alkyl group, n is or 1 or 2, n′ is 1 or 2, R′ is a hydrogenatom or a group chosen among a (C₁-C₃)alkyl group, a —NO₂ group, a—NR₁R₂ group and a (C₁-C₃)alkoxy group, with the proviso that R and R′are not simultaneously a hydrogen atom, R is not a bromine atom when R′is a hydrogen atom; (3) the compound of formula (Id)

wherein: R independently represents a hydrogen atom, a halogen atom or agroup chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group,a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group,a —NO₂ group and a —NR₁R₂ group, R₁ and R₂ are independently a hydrogenatom or a (C₁-C₃)alkyl group, n is 1 or 2, n′ is 1 or 2, R′ is ahydrogen atom or a group chosen among a (C₁-C₃)alkyl group, a —NO₂group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group, with the proviso thatwhen R′ is a hydrogen atom, R is different from a —NO₂ group, a —NH₂group or a —COOH group; (4) A compound of formula (Ii′)

wherein: R₃ is a (C₁-C₃)fluoroalkyl group or a (C₁-C₃)alkyl group, R′ isa hydrogen atom, a halogen atom or a group chosen among a (C₁-C₃)alkylgroup, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂ group, a(C₁-C₃)alkoxy group and a —CN group, R₁ and R₂ are independently ahydrogen atom or a (C₁-C₃)alkyl group, with the proviso that when R′ isa hydrogen atom, R₃ is not a methyl group or a trifluoromethyl group or(5) a pharmaceutically acceptable salt thereof.
 7. The method of claim1, wherein the compound of formula (I) is selected from the groupconsisting of: (1) a compound of formula (Ik)

wherein: R independently represents a hydrogen atom, a halogen atom or agroup chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group,a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group,a —NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy, R₁ and R₂ areindependently a hydrogen atom or a (C₁-C₃)alkyl group, n is 1 or 2, n′is 1 or 2, R′ is a hydrogen atom, a halogen atom or a group chosen amonga (C₁-C₃)alkyl group, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a—NR₁R₂ group, a (C₁-C₃)alkoxy group and a —CN group; (2) a compound offormula (Io)

wherein: R independently represents a hydrogen atom, a halogen atom or agroup chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group,a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group,a —NO₂ group, a NR₁R₂ group and a (C₁-C₃)alkoxy group, R₁ and R₂ areindependently a hydrogen atom or a (C₁-C₃)alkyl group, R′ is a hydrogenatom, a halogen atom or a group chosen among a (C₁-C₃)alkyl group, ahydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂ group, a(C₁-C₃)alkoxy group and a —CN group, R″ is a hydrogen atom or a(C₁-C₄)alkyl group, with the proviso that when R is a hydrogen atom andn′ is 1, R′ is not a hydroxyl group; (3) a compound of formula (Ij′)

wherein: R₄ is a (C₁-C₃)fluoroalkyl group or a (C₁-C₃)alkyl group, R′ isa hydrogen atom, a halogen atom or a group chosen among a (C₁-C₃)alkylgroup, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂ group, a(C₁-C₃)alkoxy group and a —CN group, with the proviso that when R′ is ahydrogen atom, R₄ is not a methyl group; (4) a compound of formula (Ij″)

wherein: R₄ is a (C₁-C₃)fluoroalkyl group or a (C₁-C₃)alkyl group, R′ isa hydrogen atom, a halogen atom or a group chosen among a(C_(p)—C₃)alkyl group, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a—NR₁R₂ group, a (C₁-C₃)alkoxy group and a —CN group, (5) a compound offormula (Ij′″)

wherein: R₄ is a (C₁-C₃)fluoroalkyl group or a (C₁-C₃)alkyl group, R′ isa hydrogen atom, a halogen atom or a group chosen among a (C₁-C₃)alkylgroup, a hydroxyl group, a —NO₂ group, a —NR₁R₂ group, a (C₁-C₃)alkoxygroup and a —CN group, with the proviso that when R′ is a chlorine atomor a hydrogen atom, R₄ is not an ethyl group or a methyl group, when R′is a methyl group or a tertio-butyl group, R₄ is not a methyl group, or(6) a pharmaceutically acceptable salt thereof.
 8. The method of claim1, wherein the compound of formula (I) is selected from the groupconsisting of: (1) a compound of formula (Ip)

wherein: R independently represents a hydrogen atom, a halogen atom or agroup chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group,a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group,a —NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group, n is 1 or 2, R′is a hydrogen atom, a halogen atom or a group chosen among a(C₁-C₃)alkyl group, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a—NR₁R₂ group, a (C₁-C₃)alkoxy group and a —CN group, with the provisothat R and R′ are not simultaneously a hydrogen atom, when n and n′ are2 then R and R′ are not simultaneously a methyl group. group; (2) acompound of formula (Ir)

wherein: R independently represent a hydrogen atom, a halogen atom or agroup chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group,a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group,a —NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group, n is 1 or 2, R′is a hydrogen atom, a halogen atom or a group chosen among a(C₁-C₃)alkyl group, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a—NR₁R₂ group, a (C₁-C₃)alkoxy group and a —CN group, R″ is a hydrogenatom or a (C₁-C₄)alkyl group, or (3) a pharmaceutically acceptable saltthereof.
 9. A method of preventing, inhibiting, or treating apathological or nonpathological condition linked with premature agingcomprising administering to an individual at least one compound chosenselected from the group consisting of (1)(8-Chloro-quinolin-2-yl)-pyridin-2-yl-amine (2)2-(Quinolin-2-ylamino)-isonicotinic acid (3)(4-Methyl-pyridin-2-yl)-quinolin-2-yl-amine (4)Pyridin-2-yl-quinolin-2-yl-amine (5)2-(8-Chloro-quinolin-2-ylamino)-isonicotinic acid (6)(8-Chloro-quinolin-2-yl)-(4-methyl-pyridin-2-yl)-amine (7)6-(Quinolin-2-ylamino)-nicotinonitrile (8)Quinolin-2-yl-(4-trifluoromethoxy-phenyl)-amine (9)Pyridin-2-yl-quinolin-3-yl-amine (10)(3-Methoxy-pyridin-2-yl)-quinolin-3-yl-amine (11)Quinolin-3-yl-(5-trifluoromethyl-pyridin-2-yl)-amine (12)(5-Nitro-pyridin-2-yl)-quinolin-3-yl-amine (13)(5-Methyl-pyridin-2-yl)-quinolin-3-yl-amine (14)2-(Quinolin-3-ylamino)-isonicotinic acid (15)Quinolin-6-yl-(5-trifluoromethyl-pyridin-2-yl)-amine (16)(6-Methyl-pyridin-2-yl)-quinolin-6-yl-amine (17)N-(6-methylpyridin-2-yl)quinolin-2-amine (18)8-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine (19)4-methyl-N-(pyridin-2-yl)quinolin-2-amine (20)4-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine (21)3-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine (22)3-methyl-N-(pyridin-2-yl)quinolin-2-amine (23)6-((4-methylquinolin-2-yl)amino)nicotinonitrile (24)6-((3-methylquinolin-2-yl)amino)nicotinonitrile (25)6-chloro-N-(4-methylpyridin-2-yl)quinolin-2-amine (26)6-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine (27)4-methyl-N-(5-nitropyridin-2-yl)quinolin-2-amine (28)N-(3-nitropyridin-2-yl)quinolin-2-amine (29)8-chloro-N-(3-nitropyridin-2-yl)quinolin-2-amine (30)2-((4-methylquinolin-2-yl)amino)nicotinonitrile (31)N-(3-methylpyridin-2-yl)quinolin-2-amine (32)N-(5-methylpyridin-2-yl)quinolin-2-amine (33)2-(quinolin-2-ylamino)isonicotinonitrile (34)N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine (35)8-chloro-N-(3-methylpyridin-2-yl)quinolin-2-amine (36)8-chloro-N-(5-methylpyridin-2-yl)quinolin-2-amine (37)8-chloro-N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine (38)N-(3-methoxypyridin-2-yl)quinolin-2-amine (39)N-(5-nitropyridin-2-yl)quinolin-2-amine (40)6-((8-chloroquinolin-2-yl)amino)nicotinonitrile (41)N-(5-fluoropyridin-2-yl)quinolin-2-amine (42)N-(6-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine (43)8-chloro-N-(5-fluoropyridin-2-yl)quinolin-2-amine (44)2-((8-chloroquinolin-2-yl)amino)nicotinic acid (45)4-methyl-N-(6-methylpyridin-2-yl)quinolin-2-amine (46)3-methyl-N-(6-methylpyridin-2-yl)quinolin-2-amine (47)5-cyano-2-(quinolin-2-ylamino)pyridin-1-ium chloride (48)2-((8-chloroquinolin-2-yl)amino)-4-methylpyridin-1-ium chloride (49)8-chloro-N-(4-ethylpyridin-2-yl)quinolin-2-amine (50)8-chloro-N-(6-ethylpyridin-2-yl)quinolin-2-amine (51)8-chloro-N-(4,6-dimethylpyridin-2-yl)quinolin-2-amine (52)6-((8-chloroquinolin-2-yl)amino)-2-methylnicotinonitrile (53)8-chloro-N-(4-chloropyridin-2-yl)quinolin-2-amine (54)8-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine (55)N-(5-bromo-4-methylpyridin-2-yl)-8-chloroquinolin-2-amine (56)8-chloro-N-(3-ethyl-6-methylpyridin-2-yl)quinolin-2-amine (57)8-fluoro-N-(4-methylpyridin-2-yl)quinolin-2-amine (58)8-bromo-N-(4-methylpyridin-2-yl)quinolin-2-amine (59) methyl6-(quinolin-2-ylamino)nicotinate (60) methyl6-[(8-chloroquinolin-2-yl)amino]pyridine-3-carboxylate (61) methyl6-[(3-methylquinolin-2-yl)amino]pyridine-3-carboxylate (62) methyl2-[(8-chloroquinolin-2-yl)amino]pyridine-3-carboxylate (63)8-methoxy-N-(4-methylpyridin-2-yl)quinolin-2-amine (64)N-(4-methylpyridin-2-yl)-5-nitroquinolin-2-amine (65)2-N-(4-methylpyridin-2-yl)quinoline-2,8-diamine (66)2-N-(4-methylpyridin-2-yl)quinoline-2,5-diamine (67) methyl6-[(4-methylquinolin-2-yl)amino]pyridine-3-carboxylate (68)8-chloro-N-[4-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine (69)2-[(8-chloroquinolin-2-yl)amino]pyridin-3-ol (70)8-chloro-N-[6-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine (71)6-chloro-N-(5-fluoropyridin-2-yl)quinolin-2-amine (72)N-(6-ethylpyridin-2-yl)-3-methylquinolin-2-amine (73)N-(5-fluoropyridin-2-yl)-3-methylquinolin-2-amine (74)3-methyl-N-[5-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine (75)4-N-(8-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine (76)N-(4-methoxyphenyl)quinolin-2-amine (77)8-chloro-N-(4-methoxyphenyl)quinolin-2-amine (78)4-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine (79)N-(4-methoxyphenyl)-3-methylquinolin-2-amine (80)3-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine (81)1-N,1-N-dimethyl-4-N-(3-methylquinolin-2-yl)benzene-1,4-diamine (82)N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine (83)N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine (84)N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine (85)N-(4-nitrophenyl)quinolin-2-amine (86)N-(3-fluorophenyl)quinolin-2-amine (87)8-chloro-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine (88)8-chloro-N-(3-fluorophenyl)quinolin-2-amine (89)2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride (90)8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine (91)3-methyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine (92)3-methyl-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine (93)3-methyl-N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine (94)8-chloro-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine (95)3-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride(96) 6-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine (97)4-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium chloride(98) 8-bromo-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine (99)8-fluoro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine (100)8-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine (101)N-(4-butoxyphenyl)-8-chloroquinolin-2-amine (102)N-(4-phenoxyphenyl)quinolin-2-amine (103)8-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine (104)8-chloro-N-[3-chloro-4-(trifluoromethoxy)phenyl]quinolin-2-amine (105)N-(6-methylpyridin-2-yl)quinolin-3-amine (106)N-(3-nitropyridin-2-yl)quinolin-3-amine (107)N-(5-methylpyridin-2-yl)quinolin-6-amine (108)N-(3-methoxypyridin-2-yl)quinolin-6-amine (109)6-chloro-N-(pyrazin-2-yl)quinolin-2-amine (110)8-bromo-N-(pyrazin-2-yl)quinolin-2-amine (111)8-methyl-N-(pyrazin-2-yl)quinolin-2-amine (112)8-chloro-N-(pyrazin-2-yl)quinolin-2-amine (113)N-(pyrazin-2-yl)quinolin-2-amine (114)4-methyl-N-(pyrazin-2-yl)quinolin-2-amine (115)3-methyl-N-(pyrazin-2-yl)quinolin-2-amine (116)8-fluoro-N-(pyrazin-2-yl)quinolin-2-amine (117)8-methoxy-N-(pyrazin-2-yl)quinolin-2-amine (118)N-(pyridin-3-yl)quinolin-3-amine (119)8-chloro-N-(pyridin-4-yl)quinolin-2-amine (120)N-(pyridin-4-yl)quinolin-2-amine (121) N-(pyridin-4-yl)quinolin-3-amine(122) N-[4-(trifluoromethoxy)phenyl]quinolin-3-amine (123)N-(4-methoxyphenyl)quinolin-3-amine (124)N-[4-(trifluoromethoxy)phenyl]quinoxalin-2-amine (125)N-[2-methyl-4-(trifluoromethoxy)phenyl]quinoxalin-2-amine (126)N-[3-(trifluoromethoxy)phenyl]quinoxalin-2-amine (127)N-[2-(trifluoromethoxy)phenyl]quinoxalin-2-amine (128)N-(pyrimidin-2-yl)quinolin-2-amine (129)8-chloro-N-(pyrimidin-2-yl)quinolin-2-amine (130)4-methyl-N-(pyrimidin-2-yl)quinolin-2-amine (131)N-(pyrazin-2-yl)quinolin-6-amine (132) N-(pyrazin-2-yl)quinolin-3-amine(133) 6-methyl-N-(naphthalen-2-yl)pyridin-2-amine (134)N-(naphthalen-2-yl)pyridin-2-amine (135)N-(pyridin-2-yl)quinoxalin-2-amine (136)N-(4-methylpyridin-2-yl)quinoxalin-2-amine (137)6-(quinoxalin-2-ylamino)pyridine-3-carbonitrile (138)N-(6-methylpyridin-2-yl)quinoxalin-2-amine (139)N-(4-methylpyridin-2-yl)-3-(trifluoromethyl)quinoxalin-2-amine (140)N-(3,5-dichloro-4-methylpyridin-2-yl)quinoxalin-2-amine (141)N-(4-methyl-3-nitropyridin-2-yl)quinoxalin-2-amine (142)N-(pyrimidin-2-yl)quinoxalin-2-amine (143)4-N,4-N-dimethyl-7-N-[4-(trifluoromethoxy)phenyl]quinoline-4,7-diamine(144) 4-(morpholin-4-yl)-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine(145) 4-methoxy-N-(pyridin-2-yl)quinolin-7-amine (146)4-methoxy-N-(4-methylpyridin-2-yl)quinolin-7-amine (147)4-N,4-N-dimethyl-7-N-(4-methylpyridin-2-yl)quinoline-4,7-diamine (148)5,8-dimethyl-N-(5-methylpyridin-2-yl)isoquinolin-6-amine (149)5,8-dimethyl-N-(5-methylpyridin-2-yl)isoquinolin-6-amine (150)N-(4-methylpyridin-2-yl)-8-nitroquinolin-2-amine (151)6-chloro-N-(6-ethylpyridin-2-yl)quinolin-2-amine (152)6-chloro-N-(5-methylpyridin-2-yl)quinolin-2-amine (153)6-chloro-N-[5-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine (154)N2-(8-chloroquinolin-2-yl)-4-methylpyridine-2,3-diamine (155)N-(4-butoxyphenyl)-3-methylquinolin-2-amine (156)4-N-(6-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine (157)8-chloro-N-(3-chloro-4-methoxyphenyl)quinolin-2-amine (158)N1-(8-chloroquinolin-2-yl)-4-(trifluoromethoxy)benzene-1,2-diamine (159)2-{4-[(8-chloroquinolin-2-yl)amino]phenoxy}ethan-1-ol (160)6-chloro-N-(4-methylpyridin-2-yl)quinoxalin-2-amine (161)N-(4-ethylpyridin-2-yl)quinoxalin-2-amine (162)N-(5-bromo-4-methylpyridin-2-yl)quinoxalin-2-amine (163)N-(4,6-dimethylpyridin-2-yl)quinoxalin-2-amine (164)[2-(quinoxalin-2-ylamino)pyridin-4-yl]methanol (165)N-(4-methyl-5-nitropyridin-2-yl)quinoxalin-2-amine (166)N-(4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)quinolin-7-amine (167)4-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine (168)N-(4-methylpyridin-2-yl)-4-(morpholin-4-yl)quinolin-7-amine and apharmaceutically acceptable salt thereof.
 10. The method of claim 9,wherein the compound is selected from the group consisting of thecompounds (1), (2), (5)-(7), (10)-(16), (18), (21)-(44), (46)-(74),(105)-(108), (124)-(130), (135)-(141), (145)-(147), (150)-(154), (159),(160)-(165), (168), and pharmaceutically acceptable hydrochloride,hydrobromide, tartrate, fumarate, citrate, trifluoroacetate, ascorbate,triflate, mesylate, tosylate, formate, acetate and malate salts thereof.11. The method of claim 1, wherein the compound is administered in apharmaceutical composition.
 12. The method of claim 10, wherein thecompound is administered in a pharmaceutical composition.
 13. The methodof claim 1, comprising administering the compound to a patient having acondition linked with premature aging.
 14. The method of claim 13,comprising orally administering the compound.
 15. The method of claim 9,comprising administering the compound to a patient having a conditionlinked with premature aging.
 16. The method of claim 15, comprisingorally administering the compound.
 17. A compound selected from thegroup consisting of: (1) a compound of formula (Ia)

wherein: R″ is a hydrogen atom or a (C₁-C₄)alkyl group n is 1, 2, or 3,n′ is 1, R independently represents a hydrogen atom, a halogen atom or agroup chosen among a (C₁-C₃)alkyl group, a—-CN group, a hydroxyl group,a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a —NO₂ group, a(C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkoxy group, R′ is a hydrogenatom, a halogen atom or a group chosen among a (C₁-C₃)alkyl group, a—COOR₁ group, and a —CN group, R₁ is a hydrogen atom or a (C₁-C₃)alkylgroup with the proviso that R and R′ are not simultaneously a hydrogenatom, when n is 1, R is not a methyl group in an ortho or para positionwith respect to Z, Z being N, when R′ is a hydrogen atom, R is not abromine atom or a chlorine atom, when R is a hydrogen atom, R′ is not amethyl or ethyl group, a —COOH group, a COOC₂H₅ group or a bromine atom,said bromine atom being in an ortho position with respect to the bondlinked to NR″; (2) a compound of formula (Ic)

wherein: R independently represents a hydrogen atom, a halogen atom or agroup chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group,a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a —NO₂ group, a —NR₁R₂ groupand a (C₁-C₃)alkoxy group, R₁ and R₂ are independently a hydrogen atomor a (C₁-C₃)alkyl group, n is 1 or 2, n′ is 1 or 2, R″ is a hydrogenatom or a (C₁-C₄)alkyl group, R′ is a hydrogen atom or a group chosenamong a (C₁-C₃)alkyl group, a —NO₂ group, a —NR₁R₂ group and a(C₁-C₃)alkoxy group, with the proviso that R and R′ are notsimultaneously a hydrogen atom, R is not a bromine atom when R′ is ahydrogen atom; (3) a compound of formula (Id)

wherein: R independently represents a hydrogen atom, a halogen atom or agroup chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group,a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group,a —NO₂ group and a —NR₁R₂ group, R₁ and R₂ are independently a hydrogenatom or a (C₁-C₃)alkyl group, n is 1 or 2, n′ is 1 or 2, R″ is ahydrogen atom or a (C₁-C₄)alkyl group, R′ is a hydrogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —NO₂ group, a —NR₁R₂ group and a(C₁-C₃)alkoxy group, with the proviso that when R′ is a hydrogen atom, Ris different from a —NO₂ group, a —NH₂ group or a —COOH group; (4) acompound of formula (Ii′)

wherein: R₃ is a (C₁-C₃)fluoroalkyl group or a (C₁-C₃)alkyl group, R′ isa hydrogen atom, a halogen atom or a group chosen among a (C₁-C₃)alkylgroup, a hydroxyl group, a —COOR₁ group, a—NO₂ group, a —NR₁R₂ group, a(C₁-C₃)alkoxy group and a —CN group, R₁ and R₂ are independently ahydrogen atom or a (C₁-C₃)alkyl group, R″ is a hydrogen atom or a(C₁-C₄)alkyl group, n′ is 1 or 2 with the proviso that when R′ is ahydrogen atom, R₃ is not a methyl group or a trifluoromethyl group (5) acompound of formula (Ik)

wherein: R independently represents a hydrogen atom, a halogen atom or agroup chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group,a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group,a —NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy, R₁ and R₂ areindependently a hydrogen atom or a (C₁-C₃)alkyl group, n is 1 or 2, n′is 1 or 2, R″ is a hydrogen atom or a (C₁-C₄)alkyl group, R′ is ahydrogen atom, a halogen atom or a group chosen among a (C₁-C₃)alkylgroup, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂ group, a(C₁-C₃)alkoxy group and a —CN group; (6) a compound of formula (Io)

wherein: R independently represents a hydrogen atom, a halogen atom or agroup chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group,a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group,a —NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group, R₁ and R₂ areindependently a hydrogen atom or a (C₁-C₃)alkyl group, n is 1, 2 or 3,n′ is 1 or 2, R′ is a hydrogen atom, a halogen atom or a group chosenamong a (C₁-C₃)alkyl group, a hydroxyl group, a —COOR₁ group, a —NO₂group, a —NR₁R₂ group, a (C₁-C₃)alkoxy group and a —CN group, R″ is ahydrogen atom or a (C₁-C₄)alkyl group, with the proviso that when R is ahydrogen atom and n′ is 1, R′ is not a hydroxyl group; (7) a compound offormula (Ij′)

wherein: R₄ is a (C₁-C₃)fluoroalkyl group or a (C₁-C₃)alkyl group, R′ isa hydrogen atom, a halogen atom or a group chosen among a (C₁-C₃)alkylgroup, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂ group, a(C₁-C₃)alkoxy group and a —CN group, R₁ and R₂ are independently ahydrogen atom or a (C₁-C₃)alkyl group, R″ is a hydrogen atom or a(C₁-C₄)alkyl group, n′ is 1 or 2, with the proviso that when R′ is ahydrogen atom, R₄ is not a methyl group; (8) a compound of formula (Ij″)

wherein: R₄ is a (C₁-C₃)fluoroalkyl group or a (C₁-C₃)alkyl group, R′ isa hydrogen atom, a halogen atom or a group chosen among a (C₁-C₃)alkylgroup, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂ group, a(C₁-C₃)alkoxy group and a —CN group, R₁ and R₂ are independently ahydrogen atom or a (C₁-C₃)alkyl group, R″ is a hydrogen atom or a(C₁-C₄)alkyl group, n′ is or 2; (9) a compound of formula (Ij′″)

wherein: R₄ is a (C₁-C₃)fluoroalkyl group or a (C₁-C₃)alkyl group, R′ isa hydrogen atom, a halogen atom or a group chosen among a (C₁-C₃)alkylgroup, a hydroxyl group, a —NO₂ group, a —NR₁R₂ group, a (C₁-C₃)alkoxygroup and a —CN group, R₁ and R₂ are independently a hydrogen atom or a(C₁-C₃)alkyl group, R″ is a hydrogen atom or a (C₁-C₄)alkyl group, n′ is1 or 2, with the proviso that when R′ is a chlorine atom or a hydrogenatom, R₄ is not an ethyl group or a methyl group, when R′ is a methylgroup or a tertio-butyl group, R₄ is not a methyl group, (10) a compoundof formula (Ip)

wherein: R independently represents a hydrogen atom, a halogen atom or agroup chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group,a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group,a —NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group, R₁ and R₂ areindependently a hydrogen atom or a (C₁-C₃)alkyl group, R″ is a hydrogenatom or a (C₁-C₄)alkyl group, n′ is 1 or 2, n is 1 or 2, R′ is ahydrogen atom, a halogen atom or a group chosen among a (C₁-C₃)alkylgroup, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂ group, a(C₁-C₃)alkoxy group and a —CN group, with the proviso that R and R′ arenot simultaneously a hydrogen atom, when n and n′ are 2 then R and R′are not simultaneously a methyl group, (11) a compound of formula (Ir)

wherein: R independently represent a hydrogen atom, a halogen atom or agroup chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group,a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group,a —NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group, R₁ and R₂ areindependently a hydrogen atom or a (C₁-C₃)alkyl group, n is 1 or 2, n′is 1 or 2, R′ is a hydrogen atom, a halogen atom or a group chosen amonga (C₁-C₃)alkyl group, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a—NR₁R₂ group, a (C₁-C₃)alkoxy group and a —CN group, R″ is a hydrogenatom or a (C₁-C₄)alkyl group, and (12) a pharmaceutically acceptablesalt thereof.
 18. A compound selected from the group consisting of: (10)(3-Methoxy-pyridin-2-yl)-quinolin-3-yl-amine (11)Quinolin-3-yl-(5-trifluoromethyl-pyridin-2-yl)-amine (12)(5-Nitro-pyridin-2-yl)-quinolin-3-yl-amine (13)(5-Methyl-pyridin-2-yl)-quinolin-3-yl-amine (14)2-(Quinolin-3-ylamino)-isonicotinic acid (15)Quinolin-6-yl-(5-trifluoromethyl-pyridin-2-yl)-amine (16)(6-Methyl-pyridin-2-yl)-quinolin-6-yl-amine (18)8-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine (21)3-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine (22)3-methyl-N-(pyridin-2-yl)quinolin-2-amine (23)6-((4-methylquinolin-2-yl)amino)nicotinonitrile (24)6-((3-methylquinolin-2-yl)amino)nicotinonitrile (25)6-chloro-N-(4-methylpyridin-2-yl)quinolin-2-amine (26)6-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine (27)4-methyl-N-(5-nitropyridin-2-yl)quinolin-2-amine (28)N-(3-nitropyridin-2-yl)quinolin-2-amine (29)8-chloro-N-(3-nitropyridin-2-yl)quinolin-2-amine (30)2-((4-methylquinolin-2-yl)amino)nicotinonitrile (31)N-(3-methylpyridin-2-yl)quinolin-2-amine (32)N-(5-methylpyridin-2-yl)quinolin-2-amine (33)2-(quinolin-2-ylamino)isonicotinonitrile (34)N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine (35)8-chloro-N-(3-methylpyridin-2-yl)quinolin-2-amine (36)8-chloro-N-(5-methylpyridin-2-yl)quinolin-2-amine (37)8-chloro-N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine (38)N-(3-methoxypyridin-2-yl)quinolin-2-amine (39)N-(5-nitropyridin-2-yl)quinolin-2-amine (40)6-((8-chloroquinolin-2-yl)amino)nicotinonitrile (41)N-(5-fluoropyridin-2-yl)quinolin-2-amine (42)N-(6-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine (43)8-chloro-N-(5-fluoropyridin-2-yl)quinolin-2-amine (44)2-((8-chloroquinolin-2-yl)amino)nicotinic acid (105)N-(6-methylpyridin-2-yl)quinolin-3-amine (106)N-(3-nitropyridin-2-yl)quinolin-3-amine (107)N-(5-methylpyridin-2-yl)quinolin-6-amine (108)N-(3-methoxypyridin-2-yl)quinolin-6-amine (124)N-[4-(trifluoromethoxy)phenyl]quinoxalin-2-amine (125)N-[2-methyl-4-(trifluoromethoxy)phenyl]quinoxalin-2-amine (126)N-[3-(trifluoromethoxy)phenyl]quinoxalin-2-amine (127)N-[2-(trifluoromethoxy)phenyl]quinoxalin-2-amine (128)N-(pyrimidin-2-yl)quinolin-2-amine (129)8-chloro-N-(pyrimidin-2-yl)quinolin-2-amine (130)4-methyl-N-(pyrimidin-2-yl)quinolin-2-amine (135)N-(pyridin-2-yl)quinoxalin-2-amine (136)N-(4-methylpyridin-2-yl)quinoxalin-2-amine (137)6-(quinoxalin-2-ylamino)pyridine-3-carbonitrile (138)N-(6-methylpyridin-2-yl)quinoxalin-2-amine (139)N-(4-methylpyridin-2-yl)-3-(trifluoromethyl)quinoxalin-2-amine (140)N-(3,5-dichloro-4-methylpyridin-2-yl)quinoxalin-2-amine (141)N-(4-methyl-3-nitropyridin-2-yl)quinoxalin-2-amine (145)4-methoxy-N-(pyridin-2-yl)quinolin-7-amine (146)4-methoxy-N-(4-methylpyridin-2-yl)quinolin-7-amine (147)4-N,4-N-dimethyl-7-N-(4-methylpyridin-2-yl)quinoline-4,7-diamine (159)2-{-4-[(8-chloroquinolin-2-yl)amino]phenoxy}ethan-1-ol (160)6-chloro-N-(4-methylpyridin-2-yl)quinoxalin-2-amine (161)N-(4-ethylpyridin-2-yl)quinoxalin-2-amine (162)N-(5-bromo-4-methylpyridin-2-yl)quinoxalin-2-amine 163)N-(4,6-dimethylpyridin-2-yl)quinoxalin-2-amine (164)[2-(quinoxalin-2-ylamino)pyridin-4-yl]methanol (165)N-(4-methyl-5-nitropyridin-2-yl)quinoxalin-2-amine and (168)N-(4-methylpyridin-2-yl)-4-(morpholin-4-yl)quinolin-7-amine andpharmaceutically acceptable salts thereof, wherein the pharmaceuticallyacceptable salts are selected from hydrochloride, hydrobromide,tartrate, fumarate, citrate, trifluoroacetate, ascorbate, triflate,mesylate, tosylate, formate, acetate and malate salts.